Pharmacologically Induced Cutaneous Squamous Cell Carcinoma: History
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Subjects: Pharmacology & Pharmacy
Contributor:
Roberto Corchado-Cobos
,
Natalia García-Sancha
,
Rogelio González-Sarmiento
,
Jesús Pérez-Losada
,
Javier Cañueto

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In addition, the high mutational burden and increased risk of CSCC in patients under immunosuppression were part of the rationale for developing the immunotherapy for CSCC that has changed the therapeutic landscape. Several drugs have been developed for CSCC treatment, but the disease may actually be induced by drugs as well. Molecular mechanisms underlie pharmacologically-induced CSCC, and a sound knowledge of them could help physicians better tackle this tumor. 

  • cutaneous squamous cell carcinoma
  • azathioprine
  • cyclosporine
  • voriconazole
  • Sonic-Hedgehog inhibitors
  • BRAF inhibitors
  • mTOR inhibitors
 

Immunosuppressive Drugs and CSCC

The immunosuppressive therapy used in organ transplant recipients (OTRs) to prevent allograft rejection promotes cutaneous infection and skin neoplasms [1][2]. The classic immunosuppressant drugs used for organ transplantation are glucocorticosteroids (prednisone and prednisolone), calcineurin inhibitors (cyclosporine and tacrolimus), and anti-proliferative agents (azathioprine and mycophenolic acid). Here we focus on cyclosporine and azathioprine.

Cyclosporine and CSCC

Cyclosporine is a calcineurin inhibitor that increases the risk of CSCC, especially under UVR [3][4][5]. Cyclosporine A reduces UVB-induced DNA damage repair and inhibits apoptosis in human keratinocytes by inhibiting the nuclear factor of activated T-cells (NFAT) [6]. Calcineurin inhibition is known to selectively induce the expression of activating transcription factor 3 (ATF3), which downregulated p53 expression and increased CSCC formation in a mouse model and in human CSCCs [7]. In vitro studies demonstrated that chronic treatment of human HaCaT keratinocytes with cyclosporine enhances AKT activation by suppressing PTEN, and promotes tumor growth of the CSCC A431 cell line in immune-deficient nude mice [8][9]. Furthermore, cyclosporine enhances epithelial-to-mesenchymal transition involving the upregulation of TGFβ signaling [10].
The increased risk of CSCC in patients under cyclosporine has led physicians to search for different options. Some studies of tacrolimus, a calcineurin inhibitor introduced to replace cyclosporine, demonstrated no difference in a comparison of overall cancer rates of the two drugs [11]; however, more recent data from a clinical trial and from in vivo studies indicate a lower skin cancer risk associated with tacrolimus [12][13]. Nevertheless, the most important drugs for preventing cyclosporine-induced CSCC development are the mTOR inhibitors.
The newest immunosuppressants used for OTRs are sirolimus (rapamycin) and everolimus. Both inhibit interleukin (IL)-2 and IL-15 via mTOR. It is not known whether these inhibitors have anticarcinogenic effects [14]. Preliminary data suggest that conversion from calcineurin inhibitors to sirolimus reduces the incidence of skin cancer in renal graft recipients [15][16], possibly because sirolimus reduces vascularization and the thickness of post-transplant CSCCs [17]. The change of therapy from calcineurin inhibitors to sirolimus in patients with one CSCC lowered the risk of a new CSCC, and metastasis events only occurred in patients who received calcineurin inhibitors [18], the effect being maintained over five years of follow-up [19]. In vivo studies of hairless mice show that sirolimus significantly increases the latency of large tumors and reduces their multiplicity. Tumors from the rapamycin group have a lower UV-signature p53 mutation rate [20]. Case reports of conversion to everolimus show a reduced likelihood of CSCC development [21].
Recent studies have shown that cyclosporine exposure upregulates IL-22R1 [22] and causes increased JAK1, STAT1, and STAT3 expression. Using ruxolitinib, an FDA-approved JAK1/2 inhibitor, in human CSCC cells and xenografts reduces proliferation and growth. This could be a feasible option for preventing CSCC in OTRs who face long-term immunosuppression [23].

Azathioprine and CSCC

In a cohort study of 361 renal transplant recipients, the immunosuppressant drug azathioprine increased the risk of CSCC 2.4-fold [24]; and in an organ transplantation cohort of 207 patients, post-transplant azathioprine treatment increased the risk of CSCC compared with controls in a dose-dependent manner [25]. A systematic review and meta-analysis of 27 studies confirmed the association of OTRs treated with azathioprine and CSCC [26]. It is clear that azathioprine enhances the effect of UVR on skin cancer risk, and indeed, it strongly induces and promotes CSCC in hairless mice exposed to UVR [27]. Azathioprine photosensitizes the skin to UVR by changing the absorption interval of DNA upon incorporation of 6-thioguanine, the active metabolite of azathioprine. UVR absorption then induces the formation of reactive oxygen species that have been linked to DNA damage and cutaneous malignancies [28][29][30]. Whole-exome sequencing has revealed a novel CSCC mutational signature, which is associated with chronic exposure to azathioprine [31].
To reduce the risk of CSCC associated with this drug, azathioprine can be replaced by mycophenolate, leading to lower levels of DNA 6-thioguanine, skin ultraviolet A (UVA) sensitivity, and DNA damage, and a lower risk of CSCC [12][32][33]. However, another study suggests that the calcineurin inhibitor tacrolimus and mycophenolate mofetil (MMF) inhibit UVB-induced DNA damage repair, demonstrating the tumor-promoting action of these immunosuppressants [34].

Voriconazole and CSCC

Voriconazole, an antifungal used to prevent and treat invasive fungal infections after lung transplantation, has been associated with an increased risk of developing CSCC [35]. Voriconazole causes photosensitivity [36] in a dose-dependent manner [37]. The mechanism underlying this may arise from a primary metabolite, voriconazole N-oxide, which absorbs UVA and UVB wavelengths [36][38]. Expression arrays of in vitro cultures of primary human keratinocytes exposed to voriconazole also show that this drug inhibits terminal epithelial differentiation pathways, resulting in poor formation of epithelial layers that are important for photoprotection, favoring its phototoxicity [39]. In vitro and in vivo assays demonstrated that voriconazole and its product inhibit catalase, raising intracellular levels of UV-associated oxidative stress and DNA damage in keratinocytes to promote skin carcinogenesis [40]. While photoprotection is fundamental for preventing CSCC, this is especially important in patients under voriconazole.
 

Targeted Therapies and CSCC

Sonic-Hedgehog Inhibitors and CSCC

Medications to treat other skin cancers, such as melanoma and basal cell carcinoma (BCC), can paradoxically lead to the development of CSCC. Vismodegib is a smoothened inhibitor (Hedgehog pathway inhibitor) that the FDA and EMA have approved for treating locally advanced and metastatic BCC [41]. The association of vismodegib with CSCC was reported in several case reports [42][43][44], and a retrospective cohort study highlighted this increased risk [45]. Some researchers disputed the latter study [46], and a subsequent paper failed to replicate such an association [47]. Furthermore, squamous metaplasia has been found in BCCs treated with vismodegib [48]. Nevertheless, there is some evidence to suggest that hedgehog inhibitors may indeed increase the risk of CSCC. The mechanism of action of vismodegib to promote CSCC is thought to be the activation of the RAS/MAPK pathway, which is responsible for CSCC progression [49].
A CSCC may arise from a BCC because both develop from the same target cell, as some authors have suggested. Two studies revealed new roles for Ptch1 that lie at the nexus between BCC and CSCC formation [50][51]. Ptch1 gene is thought to occupy a critical role in determining the basal or squamous cell lineage [51], and its polymorphisms are involved in cell fate decisions. In BCC, loss of Ptch1 activates the Sonic-Hedgehog pathway, but the overexpression of Ptch1 promotes an alternative cell-fate decision, leading to increased CSCC susceptibility [50].

BRAF Inhibitors and CSCC

BRAF is mutated in around 50% of melanomas, and some years ago, the therapeutic landscape of this tumor broadened through the development of BRAF inhibitors [52], specifically vemurafenib and dabrafenib [53]. These drugs provided greater overall survival and PFS compared with dacarbazine [54][55], but they also increased the risk of CSCC development [56][57][58]. The effectiveness of these drugs stems from their ability to attenuate the MAPK pathway, which is downstream of constitutive BRAF activation [59]. However, BRAF inhibitors are capable, paradoxically, of activating the MAPK pathway in cells containing non-mutated BRAF, and this pathway is essential for CSCC development [60][61][62][63]. The inhibition of MEK proved to be effective in preventing CSCC while on BRAF inhibitors, and thereafter BRAF inhibitors were combined with MEK inhibitors to avoid these side effects. Specifically, vemurafenib is combined with cobimetinib [64], and dabrafenib with trametinib [65]. A meta-analysis of five phase III randomized controlled trials, 17 phase II trials, and two phase IV trials [66] demonstrated that combined BRAF and MEK inhibition (trametinib) reduces the incidence of CSCC relative to BRAF monotherapy, as seen in another study [67]. More recent work demonstrated that BRAF inhibitors induce RAS mutations that are essential for MAPK activation. RAS mutations were detected in 21%–60% of lesions after BRAF inhibitor treatment in contrast to 3%–30% in normal CSCCs [60][68]. A mutational signature has been noted in squamous proliferative lesions induced by BRAF inhibitors that differs from the mutation pattern seen in spontaneous CSCCs [69]. Additionally, human papillomaviruses (HPVs) are detected more frequently in BRAF inhibitor-induced CSCCs, which means that HPV might accelerate keratinocyte oncogenesis in this subset of patients [70].
Other than MEK inhibitors, the inhibition of cyclooxygenase (COX)-2 has been evaluated as a strategy to prevent BRAF-inhibitor-mediated CSCC development. Experimental investigations that induce CSCC carcinogenesis by UVR have shown that COX-2 inhibitors (celecoxib and diclofenac) decrease prostaglandin production, thereby mitigating CSCC development [71][72]. Moreover, celecoxib delayed the onset of CSCC in a mouse model mediated by DMBA/TPA and of CSCC induced by the BRAF inhibitor PLX7420, reducing the tumor burden by 90% [73]. All the drugs that may contribute to the development of CSCC are listed in Table 1.
 
Table 1. Pharmacologically-induced CSCC.
Drug Treatment Mechanisms to Promote CSCC Options to Reduce CSCC Risk
Cyclosporine Immunosuppressant Reduces UVB-induced DNA damage repair and inhibits apoptosis by inhibiting nuclear factor of activated T-cells (NFAT) [6] Sirolimus and everolimus [15][16][17][19][20][21]
Induces the expression of ATF3, which downregulates p53 and increases CSCC formation [7]
Enhances AKT activation by suppressing PTEN and promotes tumor growth [8][9]
Enhances epithelial-to-mesenchymal transition involving the upregulation of TGFβ signaling [10]
Azathioprine Immunosuppressant Photosensitizes the skin to ultraviolet radiation (UVR) by changing the absorption interval of DNA upon incorporation of 6-thioguanine and induces the formation of reactive oxygen species [28][29][30] Mycophenolate mofetil [12][32][33]
Voriconazole Antifungal The primary metabolite, voriconazole N-oxide, absorbs UVA and UVB wavelengths and causes photosensitivity [36][37][38] Photoprotection
Inhibits terminal epithelial differentiation pathways resulting in poor formation of epithelial layers that are important for photoprotection [39]
Inhibits catalase, raising intracellular levels of UV-associated oxidative stress and DNA damage [40]
Vismodegib (Sonic-hedgehog inhibitor) Basal cell carcinoma Activates RAS-MAPK pathway [49] Close follow-up
Vemurafenib and dabrafenib (BRAF inhibitors) Melanoma Activate, paradoxically, MAPK pathway and induce RAS mutations [60][61][62][63][68] BRAF inhibitors + MEK inhibitors [64][65][66][67]  or BRAF inhibitors + cyclooxygenase (COX)-2 inhibitors [71][72][73]

 

 

This entry is adapted from the peer-reviewed paper 10.3390/ijms21082956

References

  1. Daniel Berg; Clark C. Otley; Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management.. Journal of the American Academy of Dermatology 2002, 47, 1-20, 10.1067/mjd.2002.125579.
  2. A. Mittal, O. R. Colegio; Skin Cancers in Organ Transplant Recipients.. American Journal of Transplantation 2017, 17, 2509-2530, 10.1111/ajt.14382.
  3. M.L. Price, M.J. Tidman, C.S. Ogg, D.M. MacDonald; Skin Cancer and Cyclosporine Therapy. New England Journal of Medicine 1985, 313, 1420-1420, 10.1056/nejm198511283132221.
  4. J F Thompson; T J Ryan; P S Mortimer; R P R Dawber; P J Morris; Hypertrichosis and Multiple Cutaneous Squamous Cell Carcinomas in Association with Cyclosporin a Therapy. Journal of the Royal Society of Medicine 1983, 76, 786-787, 10.1177/014107688307600915.
  5. Petter Jensen; Svein Hansen; Bjørn Møller; Torbjørn Leivestad; Per Pfeffer; Odd Geiran; Per Fauchald; Svein Simonsen; Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens.. Journal of the American Academy of Dermatology 1999, 40, 177-186, 10.1016/s0190-9622(99)70185-4.
  6. Daniel B. Yarosh; Arely V. Pena; Stephanie L. Nay; Matthew T. Canning; David A. Brown; Calcineurin Inhibitors Decrease DNA Repair and Apoptosis in Human Keratinocytes Following Ultraviolet B Irradiation. Journal of Investigative Dermatology 2005, 125, 1020-1025, 10.1111/j.0022-202x.2005.23858.x.
  7. Xunwei Wu; Bach-Cuc Nguyen; Piotr Dziunycz; Sungeun Chang; Yang Brooks; Karine Lefort; Günther F.L. Hofbauer; G. Paolo Dotto; Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature 2010, 465, 368-72, 10.1038/nature08996.
  8. Weinong Han, Mei Ming, Tong-Chuan He and Yu-Ying He; Immunosuppressive cyclosporin A activates AKT in keratinocytes through PTEN suppression: Implications in skin carcinogenesis.. Journal of Biological Chemistry 2010, 285 (15), 11369-11377, 10.1074/jbc.M109.028142..
  9. Weinong Han; Keyoumars Soltani; Mei Ming; Yu-Ying He; Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis.. Cancer Prevention Research 2012, 5, 1155-62, 10.1158/1940-6207.CAPR-12-0185-T.
  10. Stephanie B. Walsh; Jianmin Xu; Hui Xu; Ashish R. Kurundkar; Akhil Maheshwari; William E. Grizzle; Laura Timares; Conway C. Huang; Levy Kopelovich; Craig A. Elmets; et al. Cyclosporine a mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: Role of TGFβ signaling pathway. Molecular Carcinogenesis 2011, 50, 516-527, 10.1002/mc.20744.
  11. Angela C. Webster; Rebecca C Woodroffe; Rod S Taylor; Jeremy R Chapman; Jonathan Craig; Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 2005, 331, 810-810, 10.1136/bmj.38569.471007.AE.
  12. Anna E. Coghill; Lisa G. Johnson; Dan Berg; Alexa J. Resler; Nicolae Leca; Margaret M. Madeleine; Immunosuppressive Medications and Squamous Cell Skin Carcinoma: Nested Case-Control Study Within the Skin Cancer after Organ Transplant (SCOT) Cohort.. American Journal of Transplantation 2016, 16, 565-73, 10.1111/ajt.13596.
  13. H. Myron Kauffman; Wida S. Cherikh; Maureen A. McBride; Yulin Cheng; Uglas W. Hanto; Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transplant International 2006, 19, 607-620, 10.1111/j.1432-2277.2006.00330.x.
  14. Sandrine Faivre; Guido Kroemer; Eric Raymond; Current development of mTOR inhibitors as anticancer agents. Nature Reviews Drug Discovery 2006, 5, 671-688, 10.1038/nrd2062.
  15. Scott Campbell; R. Walker; S. See Tai; Q. Jiang; G. R. Russ; Randomized Controlled Trial of Sirolimus for Renal Transplant Recipients at High Risk for Nonmelanoma Skin Cancer. American Journal of Transplantation 2012, 12, 1146-1156, 10.1111/j.1600-6143.2012.04004.x.
  16. Chiara Scaglioni Tessmer; Luiza Vieira Da Silva Magalh??es; Elizete Keitel; Cristiana Valar; Diego Gnatta; Ronivan Luis Dal Pra; Fabiano Rold??o Silveira; Auri Ferreira Dos Santos; Jo??o Carlos Goldani; Valter Duro Garcia; et al. Conversion to Sirolimus in Renal Transplant Recipients with Skin Cancer. Transplantation 2006, 82, 1792-1793, 10.1097/01.tp.0000250767.67472.58.
  17. Anne-Laure Rival-Tringali; Sylvie Euvrard; Evelyne Decullier; Alain Claudy; Michel Faure; Jean Kanitakis; Conversion from calcineurin inhibitors to sirolimus reduces vascularization and thickness of post-transplant cutaneous squamous cell carcinomas.. Anticancer Research 2009, 29, 1927-1932, .
  18. Sylvie Euvrard; Emmanuel Morelon; Lionel Rostaing; Éric Goffin; Anabelle Brocard; Isabelle Tromme; Nilufer Broeders; Véronique Del Marmol; Valérie Chatelet; Anne Dompmartin; et al. Sirolimus and Secondary Skin-Cancer Prevention in Kidney Transplantation. New England Journal of Medicine 2012, 367, 329-339, 10.1056/nejmoa1204166.
  19. Jacques Dantal; Emmanuel Morelon; Lionel Rostaing; Eric Goffin; Anabelle Brocard; Isabelle Tromme; Nilufer Broeders; Véronique Del Marmol; Valérie Chatelet; Anne Dompmartin; et al. Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results. Journal of Clinical Oncology 2018, 36, 2612-2620, 10.1200/jco.2017.76.6691.
  20. F. R. De Gruijl; G.E. Koehl; P. Voskamp; A. Strik; H.G. Rebel; A. Gaumann; J.W. De Fijter; C.P. Tensen; J.N. Bouwes Bavinck; E.K. Geissler; et al. Early and late effects of the immunosuppressants rapamycin and mycophenolate mofetil on UV carcinogenesis. International Journal of Cancer 2010, 127, 796-804, 10.1002/ijc.25097.
  21. Hallvard Holdaas; Paolo De Simone; Andreas Zuckermann; Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update. Journal of Transplantation 2016, 2016, 1-11, 10.1155/2016/4369574.
  22. Melody Abikhair; Hiroshi Mitsui; Valerie Yanofsky; Nazanin Roudiani; Channa Ovits; Teddy Bryan; Tatiana M. Oberyszyn; Kathleen L. Tober; Juana Gonzalez; James G. Krueger; et al. Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22.. JCI Insight 2016, 1, e86434, 10.1172/jci.insight.86434.
  23. Melody Abikhair Burgo; Nazanin Roudiani; Jie Chen; Alexis L. Santana; Nicole Doudican; Charlotte Proby; Diane Felsen; John Carucci; Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma.. JCI Insight 2018, 3, e120750, 10.1172/jci.insight.120750.
  24. Helen M Ramsay; Anthony Fryer; Carmel Hawley; Andrew G Smith; David L Nicol; Paul N Harden; Factors associated with nonmelanoma skin cancer following renal transplantation in Queensland, Australia. Journal of the American Academy of Dermatology 2003, 49, 397-406, 10.1067/s0190-9622(03)00902-2.
  25. Åsa Ingvar; Karin Ekström Smedby; Bernt Lindelöf; Pia Fernberg; Rino Bellocco; Gunnar Tufveson; Petter Höglund; Johanna Adami; Immunosuppressive treatment after solid organ transplantation and risk of post-transplant cutaneous squamous cell carcinoma. Nephrology Dialysis Transplantation 2009, 25, 2764-2771, 10.1093/ndt/gfp425.
  26. Z. Jiyad; Catherine Olsen; M. T. Burke; N. M. Isbel; A.C. Green; Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis. American Journal of Transplantation 2016, 16, 3490-3503, 10.1111/ajt.13863.
  27. Graham E. Kelly; William Meikle; A. G. Ross Sheil; EFFECTS OF IMMUNOSUPPRESSIVE THERAPY ON THE INDUCTION OF SKIN TUMORS BY ULTRAVIOLET IRRADIATION IN HAIRLESS MICE. Transplantation 1987, 44, 429-433, 10.1097/00007890-198709000-00021.
  28. Peter O'donovan; Conal M. Perrett; Xiaohong Zhang; Beatriz Montaner; Yao Xu; C.A. Harwood; Jane M. McGregor; Susan L. Walker; Fumio Hanaoka; Peter Karran; et al. Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage. Science 2005, 309, 1871-1874, 10.1126/science.1114233.
  29. C.M. Perrett; P. O’Donovan; Jane Warwick; C.A. Harwood; S.L. Walker; P. Karran; J.M. McGregor; Azathioprine treatment photosensitizes human skin to ultraviolet A radiation. British Journal of Dermatology 2008, 159, 198-204, 10.1111/j.1365-2133.2008.08610.x.
  30. Natalie R. Attard; Peter Karran; UVA photosensitization of thiopurines and skin cancer in organ transplant recipients. Photochem. Photobiol. Sci. 2012, 11, 62-68, 10.1039/c1pp05194f.
  31. Gareth Inman; Jun Wang; Ai Nagano; Ludmil B. Alexandrov; Karin J. Purdie; Richard G. Taylor; Victoria Sherwood; Jason Thomson; Sarah Hogan; Lindsay C. Spender; et al. The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature.. Nature Communications 2018, 9, 3667, 10.1038/s41467-018-06027-1.
  32. Günther F.L. Hofbauer; N. R. Attard; C.A. Harwood; J. M. McGregor; P. Dziunycz; G. Iotzova-Weiss; G. Straub; R. Meyer; Y. Kamenisch; M. Berneburg; et al. Reversal of UVA Skin Photosensitivity and DNA Damage in Kidney Transplant Recipients by Replacing Azathioprine. American Journal of Transplantation 2011, 12, 218-225, 10.1111/j.1600-6143.2011.03751.x.
  33. Martin Voß; Elsemieke I. Plasmeijer; Barbara C. Van Bemmel; Wim Van Der Bij; Nina S. Klaver; Michiel E. Erasmus; Geertruida H. De Bock; Erik A.M. Verschuuren; Emőke Rácz; Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation. The Journal of Heart and Lung Transplantation 2018, 37, 853-859, 10.1016/j.healun.2018.03.012.
  34. Mei Ming; Baozhong Zhao; Lei Qiang; Yu-Ying He; Effect of immunosuppressants tacrolimus and mycophenolate mofetil on the keratinocyte UVB response.. Photochemistry and Photobiology 2014, 91, 242-7, 10.1111/php.12318.
  35. Ashley Feist; Roy Lee; Stephanie Osborne; James Lane; Gordon L Yung; Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole. The Journal of Heart and Lung Transplantation 2012, 31, 1177-1181, 10.1016/j.healun.2012.05.003.
  36. Edward W. Cowen; Josephine C. Nguyen; Daniel D. Miller; Diana McShane; S.T. Arron; Neil S. Prose; Maria L. Turner; Lindy P. Fox; Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. Journal of the American Academy of Dermatology 2009, 62, 31-7, 10.1016/j.jaad.2009.09.033.
  37. Jonathan P. Singer; Andreas Boker; Christopher Metchnikoff; Maxwell Binstock; Rebecca Boettger; Jeffrey A. Golden; David V. Glidden; S.T. Arron; High cumulative dose exposure to voriconazole is associated with cutaneous squamous cell carcinoma in lung transplant recipients.. The Journal of Heart and Lung Transplantation 2012, 31, 694-9, 10.1016/j.healun.2012.02.033.
  38. Norie Murayama; Naoko Imai; Takahisa Nakane; Makiko Shimizu; Hiroshi Yamazaki; Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. Biochemical Pharmacology 2007, 73, 2020-2026, 10.1016/j.bcp.2007.03.012.
  39. M. Mansh; L. Ing; M. Dimon; A. Celli; T.M. Mauro; S.T. Arron; Voriconazole exposure regulates distinct cell-cycle and terminal differentiation pathways in primary human keratinocytes.. British Journal of Dermatology 2017, 176, 816-820, 10.1111/bjd.14838.
  40. Vivian Lee; Michael D. Gober; Hasan Bashir; Conor O'day; Ian A. Blair; Clementina Mesaros; Liwei Weng; Andrew Huang; Aaron Chen; Rachel Tang; et al. Voriconazole enhances UV‐induced DNA damage by inhibiting catalase and promoting oxidative stress. Experimental Dermatology 2019, 29, 29-38, 10.1111/exd.14038.
  41. N. Basset-Seguin; Axel Hauschild; Rainer Kunstfeld; Jean-Jacques Grob; B. Dréno; Laurent Mortier; Paolo Antonio Ascierto; Lisa Licitra; C. Dutriaux; L. Thomas; et al. Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial.. European Journal of Cancer 2017, 86, 334-348, 10.1016/j.ejca.2017.08.022.
  42. C. Saintes; M. Saint-Jean; A. Brocard; Lucie Peuvrel; J.J. Renaut; A. Khammari; G. Quéreux; B. Dréno; Development of squamous cell carcinoma into basal cell carcinoma under treatment with Vismodegib. Journal of the European Academy of Dermatology and Venereology 2014, 29, 1006-1009, 10.1111/jdv.12526.
  43. Sumaira Aasi; Rona Silkiss; Jean Y. Tang; Ashley Wysong; Andy Liu; Ervin Epstein; Anthony E. Oro; Anne Lynn S. Chang; New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases.. JAMA Dermatology 2013, 149, 242-3, 10.1001/jamadermatol.2013.1798.
  44. Amy Iarrobino; Jane L. Messina; Ragini Kudchadkar; Vernon K. Sondak; Emergence of a squamous cell carcinoma phenotype following treatment of metastatic basal cell carcinoma with vismodegib. Journal of the American Academy of Dermatology 2013, 69, e33-e34, 10.1016/j.jaad.2013.01.023.
  45. Shalini V. Mohan; Julia Chang; Shufeng Li; A. Solomon Henry; Douglas J. Wood; Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma. JAMA Dermatology 2016, 152, 527, 10.1001/jamadermatol.2015.4330.
  46. Susana Puig; Francesca Sampogna; Antonio Tejera-Vaquerizo; Study on the Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma: Not a Case-Control Study.. JAMA Dermatology 2016, 152, 1172-1173, 10.1001/jamadermatol.2016.2428.
  47. Tina Bhutani; Michael Abrouk; Camelia S. Sima; Natalia Sadetsky; Jeannie Hou; Ivor Caro; Mary-Margaret Chren; S.T. Arron; Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib. Journal of the American Academy of Dermatology 2017, 77, 713-718, 10.1016/j.jaad.2017.03.038.
  48. B. Bancalari; B. Llombart; C. Serra-Guillén; E. Bernia; C. Requena; E. Nagore; V. Traves; L. Calomarde; A. Diago; O. Sanmartín; et al. Histologic Changes During Treatment With Vismodegib in Locally Advanced Basal Cell Carcinoma. The American Journal of Dermatopathology 2019, 41, 711-717, 10.1097/dad.0000000000001384.
  49. Xuesong Zhao; Tatyana Ponomaryov; Kimberly J. Ornell; Pengcheng Zhou; Sukriti K. Dabral; Ekaterina Pak; Wei Li; Scott X. Atwood; Ramon J. Whitson; Anne Lynn S. Chang; et al. RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors.. Cancer Research 2015, 75, 3623-35, 10.1158/0008-5472.CAN-14-2999-T.
  50. Hio Chung Kang; Yuichi Wakabayashi; Kuang-Yu Jen; Jian-Hua Mao; Vassilis Zoumpourlis; Reyno Del Rosario; Allan Balmain; Ptch1 Overexpression Drives Skin Carcinogenesis and Developmental Defects in K14PtchFVB Mice. Journal of Investigative Dermatology 2012, 133, 1311-20, 10.1038/jid.2012.419.
  51. Yuichi Wakabayashi; Jian-Hua Mao; Ken Brown; Michael Girardi; Allan Balmain; Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 2007, 445, 761-765, 10.1038/nature05489.
  52. Antoni Ribas; Keith T. Flaherty; BRAF targeted therapy changes the treatment paradigm in melanoma. Nature Reviews Clinical Oncology 2011, 8, 426-433, 10.1038/nrclinonc.2011.69.
  53. L Heinzerling; M Baiter; S Kühnapfel; G Schuler; P Keikavoussi; A Agaimy; F Kiesewetter; A Hartmann; R Schneider-Stock; Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations. British Journal of Cancer 2013, 109, 2833-2841, 10.1038/bjc.2013.622.
  54. P. B. Chapman; Axel Hauschild; Caroline Robert; John B. Haanen; Paolo Ascierto; James Larkin; Reinhard Dummer; C. Garbe; Alessandro Testori; Michele Maio; et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.. New England Journal of Medicine 2011, 364, 2507-16, 10.1056/NEJMoa1103782.
  55. Axel Hauschild; Jean-Jacques Grob; Lev V Demidov; Thomas Jouary; Ralf Gutzmer; Michael Millward; Piotr Rutkowski; Christian U Blank; Wilson H Miller; Eckhart Kaempgen; et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet 2012, 380, 358-365, 10.1016/s0140-6736(12)60868-x.
  56. Rachael Anforth; Alexander M. Menzies; Karen Byth; Giuliana Carlos; Shaun Chou; Raghwa Sharma; Richard A. Scolyer; Richard Kefford; Georgina V. Long; Pablo Fernandez-Penas; et al. Factors influencing the development of cutaneous squamous cell carcinoma in patients on BRAF inhibitor therapy. Journal of the American Academy of Dermatology 2015, 72, 809-815.e1, 10.1016/j.jaad.2015.01.018.
  57. Kari E. Sufficool; Donna M. Hepper; Gerald P. Linette; Eva A. Hurst; Dongsi Lu; Anne C. Lind; Lynn A. Cornelius; Histopathologic characteristics of therapy-associated cutaneous neoplasms with vemurafenib, a selective BRAF kinase inhibitor, used in the treatment of melanoma. Journal of Cutaneous Pathology 2014, 41, 568-575, 10.1111/cup.12346.
  58. Nathan Harvey; Michael Millward; Benjamin A. Wood; Squamoproliferative Lesions Arising in the Setting of BRAF Inhibition. The American Journal of Dermatopathology 2012, 34, 822-826, 10.1097/dad.0b013e3182604873.
  59. Gideon Bollag; James Tsai; Jiazhong Zhang; Chao Zhang; Prabha Ibrahim; Keith Nolop; Peter Hirth; Vemurafenib: the first drug approved for BRAF-mutant cancer. Nature Reviews Drug Discovery 2012, 11, 873-886, 10.1038/nrd3847.
  60. Fei Su; Amaya Viros; Carla Milagre; Kerstin Trunzer; Gideon Bollag; Olivia Spleiss; Jorge S. Reis-Filho; Xiangju Kong; Richard C. Koya; Keith T. Flaherty; et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.. New England Journal of Medicine 2012, 366, 207-15, 10.1056/NEJMoa1105358.
  61. Geoffrey T. Gibney; Jane L. Messina; Inna V. Fedorenko; Vernon K. Sondak; Keiran S.M. Smalley; Paradoxical oncogenesis--the long-term effects of BRAF inhibition in melanoma.. Nature Reviews Clinical Oncology 2013, 10, 390-9, 10.1038/nrclinonc.2013.83.
  62. Georgia Hatzivassiliou; Kyung Song; Ivana Yen; Barbara J. Brandhuber; Daniel Anderson; Ryan Alvarado; Mary J. C. Ludlam; David Stokoe; Susan L. Gloor; Guy Vigers; et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010, 464, 431-435, 10.1038/nature08833.
  63. Poulikos I. Poulikakos; Chao Zhang; Gideon Bollag; Kevan M. Shokat; Neal Rosen; RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010, 464, 427-30, 10.1038/nature08902.
  64. James Larkin; Paolo Antonio Ascierto; B. Dréno; Victoria Atkinson; Gabriella Liszkay; Michele Maio; Mario Mandalà; Lev Demidov; Daniil Stroyakovskiy; L. Thomas; et al. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma. New England Journal of Medicine 2014, 371, 1867-1876, 10.1056/nejmoa1408868.
  65. Keith T. Flaherty; Jeffery R. Infante; Aizati Daud; René Gonzalez; Richard Kefford; Jeffrey Sosman; Omid Hamid; Lynn Schuchter; Jonathan Cebon; Nageatte Ibrahim; et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.. New England Journal of Medicine 2012, 367, 1694-703, 10.1056/NEJMoa1210093.
  66. Ling Peng; Yina Wang; Yun Hong; Xianghua Ye; Peng Shi; Junyan Zhang; Qiong Zhao; Incidence and relative risk of cutaneous squamous cell carcinoma with single-agent BRAF inhibitor and dual BRAF/MEK inhibitors in cancer patients: a meta-analysis. Oncotarget 2017, 8, 83280-83291, 10.18632/oncotarget.21059.
  67. M. Sanlorenzo; Aditi Choudhry; Igor Vujic; Christian Posch; Kim Chong; Katia Johnston; Melissa Meier; Simona Osella-Abate; Pietro Quaglino; Aizati Daud; et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma.. Journal of the American Academy of Dermatology 2014, 71, 1102-1109.e1, 10.1016/j.jaad.2014.09.002.
  68. Patrick A. Oberholzer; Damien Kee; Piotr Dziunycz; Antje Sucker; Nyam Kamsukom; Robert Jones; Christine Roden; Clinton J. Chalk; Kristin Ardlie; Emanuele Palescandolo; et al. RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors. Journal of Clinical Oncology 2012, 30, 316-321, 10.1200/jco.2011.36.7680.
  69. Britt Clynick; Tania Tabone; Kathryn Fuller; Wendy Erber; Katie Meehan; Michael Millward; Benjamin A. Wood; Nathan Harvey; Kathy Fuller; Mutational Analysis of BRAF Inhibitor–Associated Squamoproliferative Lesions. The Journal of Molecular Diagnostics 2015, 17, 644-651, 10.1016/j.jmoldx.2015.05.009.
  70. Daniel N. Cohen; Steven K. Lawson; Aaron C. Shaver; Liping Du; Harrison P. Nguyen; Qin He; Douglas B. Johnson; Wilfred A. Lumbang; Brent R. Moody; James L. Prescott; et al. Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy.. Clinical Cancer Research 2015, 21, 2624-34, 10.1158/1078-0432.CCR-14-2667.
  71. A P Pentland; John W. Schoggins; Glynis A. Scott; Kanwar Nasir M. Khan; Rujing Han; Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition.. Carcinogenesis 1999, 20, 1939-1944, 10.1093/carcin/20.10.1939.
  72. Erin M. Burns; Kathleen L. Tober; Judith A. Riggenbach; Jonathan S. Schick; Keith N. Lamping; Nna F. Kusewitt; Gregory S. Young; Tatiana Oberyszyn; Preventative topical diclofenac treatment differentially decreases tumor burden in male and female Skh-1 mice in a model of UVB-induced cutaneous squamous cell carcinoma.. Carcinogenesis 2012, 34, 370-7, 10.1093/carcin/bgs349.
  73. Helena Escuin-Ordinas; Mohammad Atefi; Yong Fu; Ashley Cass; Charles Ng; Rong Rong Huang; Sharona Yashar; Begonya Comin-Anduix; Earl Avramis; Alistair J. Cochran; et al. COX‐2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors. Molecular Oncology 2013, 8, 250-260, 10.1016/j.molonc.2013.11.005.
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