Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 although a great amount of evidence confirms that AXL is a key element of breast cell tumorigenesis, its clinical implications are still limited. Many inhibitors in use are multi-targets, and AXL’s selective inhibitors are still in pre-clinical trials
Italia Falcone
 + 2105 word(s) 2105 2020-11-23 09:57:54 |
2 although a great amount of evidence confirms that AXL is a key element of breast cell tumorigenesis, its clinical implications are still limited. Many inhibitors in use are multi-targets, and AXL’s selective inhibitors are still in pre-clinical trials
Italia Falcone
 -75 word(s) 2030 2020-11-23 10:31:17 | |
3 Format correct
Vicky Zhou
 Meta information modification 2030 2020-11-24 04:18:25 | |
4 Format correct
Vicky Zhou
 -37 word(s) 1993 2020-11-24 04:18:57 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Falcone, I.; Conciatori, F.; Bazzichetto, C.; Bria, E.; Carbognin, L.; Malaguti, P.; Ferretti, G.; Cognetti, F.; Milella, M.; Ciuffreda, L. AXL Receptor in Breast Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/3163 (accessed on 17 November 2024).
Falcone I, Conciatori F, Bazzichetto C, Bria E, Carbognin L, Malaguti P, et al. AXL Receptor in Breast Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/3163. Accessed November 17, 2024.
Falcone, Italia, Fabiana Conciatori, Chiara Bazzichetto, Emilio Bria, Luisa Carbognin, Paola Malaguti, Gianluigi Ferretti, Francesco Cognetti, Michele Milella, Ludovica Ciuffreda. "AXL Receptor in Breast Cancer" Encyclopedia, https://encyclopedia.pub/entry/3163 (accessed November 17, 2024).
Falcone, I., Conciatori, F., Bazzichetto, C., Bria, E., Carbognin, L., Malaguti, P., Ferretti, G., Cognetti, F., Milella, M., & Ciuffreda, L. (2020, November 23). AXL Receptor in Breast Cancer. In Encyclopedia. https://encyclopedia.pub/entry/3163
Falcone, Italia, et al. "AXL Receptor in Breast Cancer." Encyclopedia. Web. 23 November, 2020.
AXL Receptor in Breast Cancer
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms21228419

Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family.

AXL breast cancer biomarker

1. Introduction

In the oncological field, therapeutic scenarios are multiple and have evolved considerably in recent years. Unspecific treatments, such as chemotherapy, have given way to the new pharmacological frontiers of targeted therapy and immunotherapy. The discovery of new molecular targets and the well-established evidence of the tight interconnection between tumor cells and the microenvironment have revolutionized the clinical management of patients. Human epidermal growth factor receptor 2 (HER2) or estrogen receptor and (ER)/PROGESTERONE RECEPTOR (PR)-positive tumors have benefited from targeted treatments, but particularly aggressive forms have yet to find the optimal therapeutic approach. For example, for triple-negative breast cancer (TNBC), the research for new biomarkers is always open. AXL, especially in this molecular background, performs many oncogenic functions and is considered a potential marker in which to invest. However, although a great amount of evidence confirms that AXL is a key element of breast cell tumorigenesis, its clinical implications are still limited. Many inhibitors currently in use are multi-targets, and AXL’s selective inhibitors are still in pre-clinical trials. Therefore, the necessity to better explore the molecular implications of AXL and its involvement in the immune response becomes even more important in order to develop its selective and effective molecules.

Currently, breast cancer is the second leading cause of oncological death in the female population globally and represents about 30% of invasive tumors in women [1][2]. Although significant advances have been made in the treatment of this pathology, phenomena such as metastasis and drug resistance still remain unresolved. Indeed, even if targeted therapy and immunotherapy have greatly improved the life expectancy of many patients, they have not bypassed these problems at the basis of many cancer deaths. The use of high performance “omics” technologies, in recent years, has accelerated the identification of new molecular targets able to perform the dual function of predictive and/or prognostic factors [3]. Moreover, an extensive study of the biomarkers’ action mechanisms is desirable to allow the development of new inhibitors.

In recent years, it has emerged that receptor and non-receptor tyrosine kinases (TKs) are often overexpressed/mutated in many tumor models, including breast cancer, representing a possible molecular target in clinical cancer therapy [4]. TKs are a big family of proteins that perform a mediator role between the inside and outside of cell. Their activation regulates cell differentiation, proliferation, apoptosis and metabolism [5][6][7]. Receptor TKs (RTKs) include 20 families classifiable according to amino acid sequence within the kinase domain and structural analogism within extracellular regions [8][9][10]. The ligand/receptor interaction triggers a biochemical reaction cascade that culminates in tyrosine residue phosphorylation on different substrates [9]. RTKs’ subfamily is composed of TYRO-3 (or Sky), AXL (or UFO) and MER (or Eyk, Nym and Tyro12) (TAM) receptors, essentially formed by an extracellular region and a cytoplasmic kinase domain. Growth arrest-specific 6 (GAS6), protein S1 (PROS1), Tubby, Tubby-like protein 1 (TULP-1) and Galectin-3 are the most important ligands of TAMs [11][12]. Despite its highest affinity to AXL, GAS6 recognizes and binds TYRO-3 and MER also, while PROS1 seems to interact only with TYRO-3 and MER [12][13]. Moreover, TULP-1 binds all three TAM receptors and Tubby and Galectin-3 only recognize MER [14][15][16]. TAM receptors are overexpressed in several human malignancies, including leukemia, melanoma, breast, lung, gastric and colon cancers, promoting upregulation of pro-survival pathways [17][18]. All members of the TAM family are involved in the development and progression of different forms of cancer, such as lung and colon tumors [19][20]; however, in the genesis of the breast cancers, AXL is particularly involved; indeed, in this tumor context, it results often dysregulated and its overexpression is associated to unfavorable outcomes for patients. In addition, AXL contributes to all stages of malignant breast cell transformation, especially by affecting the transition to a mesenchymal and invasive state [21]. Therefore, several inhibitors for this receptor are developed, although its high structural affinity with other RTKs makes it difficult to produce specific drugs. BGB324 (Bemcentinib or R428) is probably the most selective AXL inhibitor and, recently, in combination with pembrolizumab, was implicated in clinical trials for triple-negative breast cancer (TNBC) and adenocarcinoma [22].

2. AXL Inhibition in Breast Cancer Treatment

AXL inhibitors are classified, according to their action mechanisms, into three categories: (1) drugs that modulate and inhibit the kinase activity of the receptor; (2) specific antibodies that prevent the AXL dimerization and activation; (3) drugs that recognize and bind GAS6 [13].

The most important AXL inhibitors are summarized and described in Table 1.

Table 1. AXL inhibitors. Several AXL inhibitors (selective or not) are involved in the treatment of breast cancer. Many of them, however, are still in preclinical development.

Selective Inhibitors
  Target(s) Function(s) Field(s) Reference(s)
BGB324
(Bemcentinib or R428)		 AXL ATP-competitive AXL inhibitor that promotes apoptosis and reduces cell growth and metastasis Preclinical and clinical [23][24][25][26][27][28]
NA80X-1 AXL Selective AXL inhibitor that decreases cell motility and invasion Preclinical [29]
YW327.6S2 AXL Monoclonal antibody that inhibits GAS6/AXL interaction Preclinical [30]
GL21-T AXL RNA-based aptamer that blocks AXL’s catalytic activity and inhibits mobility and metastasis Preclinical [31][32]
DN10764
(AZD7762)		 AXL
ChKs		 Selective AXL inhibitor that decreases cell proliferation, invasion and migration and induces apoptosis Preclinical [33][34]
SGI-7079 AXL Selective AXL inhibitor that decreases cell proliferation and metastasis Preclinical [35]
Non-Selective Inhibitors
Rebastinib
(DCC-2036)		 MET
VEGFR2
SRC
AXL		 Multi-target inhibitor that decreases cell proliferation, invasion, migration and EMT Preclinical and Clinical [36][37]
Cabozantinib (XL184) RET
VEGFR2
Flt 1-3-4
Tie2
MET
AXL		 Multi-target inhibitor that decreases cellular invasion and promotes immune system activation Preclinical and clinical [38][39][40][41][42][43]
Foretinib (XL880 or GSK-1363089) MET
RET
VEGFR2
AXL		 Multi-target inhibitor that restores the response to lapatinib in HER2+ context Preclinical and clinical [44]
Merestinib (LY2801653) MET
MST1R
MKNK1/2
AXL		 Multi-target agent that inhibits angiogenesis and mitosis Preclinical and clinical [45][46]
Bosutinib (SKI-606) SRC
Abl
MEK
BMX
AXL		 Multi-target inhibitors that decreases invasion, metastasis and tumor differentiation Preclinical and clinical [47][48][49]
Crizotinib (PF-02341066) MET
ALK
ROS1
AXL		 ATP-competitive agent that inhibits cell proliferation Preclinical and clinical [50][51]

2.1. AXL Selective Inhibitors

BGB324 (Bemcentinib or R428) is the more selective ATP-competitive inhibitor of AXL (IC50 = 14 nM) and was the first to enter clinical trials to treat several cancer forms, such as TNBC tumors, metastatic melanoma and NSCLC. By blocking AXL autophosphorylation on tyrosine residue Y821, in vitro, it induces apoptosis, inhibits cancer cell invasion and reverts erlotinib resistance in TNBC cells; in vivo, BGB324 reduces cancer metastasis [23][24][25][26]. In a recent preclinical study, BGB324 was tested in combination with auranofin, a gold phosphine derivative, initially used for the treatment of rheumatoid arthritis and also studied for the treatment of the other diseases, such as breast cancer. It is a thioredoxin reductase inhibitor and appears to induce apoptosis through PI3K pathway inhibition [27]. The authors of this study have observed that in different breast cancer settings (MDA-MB231 and MCF7), the combination of BGB234 and auranofin reduced cell growth by inducing apoptosis, mediated by increased levels of Bcl-2-associated X-protein (BAX) [28]. Recently, BGB324 was implicated in a phase II clinical trial (NCT03184558) for TNBC and inflammatory breast cancers, in combination with pembrolizumab; however, the results have not yet been released [22]. Other selective AXL inhibitors have been recently developed and have validated their efficacy in the preclinical field. NA80X-1 determines a decrease in cell motility and invasion in MDA-MB435 cells [29]. YW327.6S2 represents a potent anti-AXL monoclonal antibody that recognizes and binds AXL with high affinity. This antibody, by preventing the GAS6 interaction with the receptor, inhibits AXL activation and its downstream signaling [30]. GL21-T is an RNA-based aptamer which blocks AXL catalytic activity through interaction with the receptor extracellular domain [31]. In a recent preclinical study, the inhibitory action of this drug was evaluated in combination with the anti-metastatic miRNA148b. The authors have created a conjugate (AXL-148b) able to work only in positive AXL contexts. In vitro, by increasing the expression levels of miRNA148b, the conjugate has reduced the formation and mobility of mammospheres; in vivo, AXL-148b has blocked metastasis formation [32]. DN10764 (or AZD7762), developed as selective inhibitor of checkpoint kinases (ChKs) 1 and 2, is also involved in AXL downregulation. In a preclinical field study, DN10764 inhibited, in both vitro and in vivo experiments, AXL-dependent cell proliferation, invasion and migration and also induces apoptosis through caspases 3/7 activation [33][34]. SGI-7079 is another selective AXL inhibitor which, however, also targets the other members of the TAM family; in vitro experiments showed that it decreased cell proliferation and metastasis [35].

2.2. Multi-Targets Inhibitors

Rebastinib (or DCC-2036) is a multi-target inhibitor involved in the regulation of cell proliferation, invasion, migration and EMT processes by blocking the activity of several TKs, such as MET, vascular endothelial growth factor receptor 2 (VEGFR2), SRC and AXL. A recent in vitro and in vivo study has shown that in TNBCs (little responsive to hormonal and anti-HER2 therapies), rebastinib inhibited cell proliferation, invasion and EMT more efficiently as compared to other drugs used for breast cancer treatment. In addition, its combination with lapatinib or cisplatin significantly decreased the growth of TNBC cells [36]. Although it does not have a single site of action, rebastinib seems to carry out its inhibitory function mainly on AXL and its downstream targets. Indeed, the drug decreases cell growth only in murine models inoculated with TNBC characterized by high levels of AXL [37].

Cabozantinib (or XL184) recognizes and blocks many RTKs, such as Rearranged during Transfection (RET), VEGFR2, Kit, fms-related tyrosine kinases (Flt) 1, 3 and 4, tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2), MET and AXL [38]. It is implicated in the treatment of several solid malignancies, such as renal cell carcinoma, medullary thyroid, NSCLC and TNBC tumors, by decreasing the metastatic and invasive potential of cancer cells. In a recent phase II trial (NCT01738438) conducted on metastatic TNBC patients, cabozantinib administration led to a clinical benefit of 34%, determining a median PFS of 2.0 months; moreover, cabozantinib treatment has determined quite encouraging results in terms of immune system activation. Indeed, patients treated with this drug showed higher circulating levels of CD8+ T lymphocytes and a greater activation of antitumor immunity. However, these results are still not very consistent and need further investigation [39][40][41][42][43].

Foretinib (XL880 or GSK-1363089) is another multi-kinase inhibitor which blocks AXL, MET, RET and VEGFR2 activity. In HER2-amplified breast tumors, it restores sensitivity to lapatinib and trastuzumab in resistant cells with high levels of AXL. AXL and HER3 interaction bypasses the lapatinib-mediated HER2 block, promoting PI3K/AKT pathway hyperactivation and drug resistance. AXL inhibition, mediated by foretinib, removes the AXL/HER3 interconnection and restores cell response to lapatinib [44]. In a phase II clinical trial (NCT01147484), 46% of enrolled TNBC patients benefited from foretinib treatment [22][52].

Merestinib (or LY2801653) is a small molecule kinase inhibitor which targets AXL, MET, macrophage-stimulating protein receptor (MST1R) and MAP kinase-interacting serine/threonine kinase 1 (MKNK1/2). In vitro and in vivo experiments have shown that merestinib inhibits angiogenesis and mitosis [45][46].

Bosutinib (or SKI-606), originally identified as an SRC and Abelson murine leukemia viral oncogene (Abl) kinase inhibitor, is also a powerful inhibitor of AXL, Mitogen-activated protein kinase kinase (MEK) and BMX [47]. In breast cancer, it regulates invasion, metastasis and tumor differentiation [48][49]. Bosutinib is implicated, for breast tumors, in several clinical trials [22].

Crizotinib (or PF-02341066) is an ATP-competitive small-molecule inhibitor which blocks MET, anaplastic lymphoma receptor tyrosine kinase (ALK), c-ros oncogene 1 receptor tyrosine kinase (ROS1) and AXL. In breast cancer cell lines, it inhibits cellular proliferation [50][51]. As described for the other non-selective inhibitors, crizotinib is also involved in several clinical trials as a modulator of other molecular targets [22].

References

  1. Malhotra, G.K.; Zhao, X.; Band, H.; Band, V. Histological, molecular and functional subtypes of breast cancers. Cancer Biol. 2010, 10, 955–960.
  2. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34.
  3. Olivier, M.; Asmis, R.; Hawkins, G.A.; Howard, T.D.; Cox, L.A. The Need for Multi-Omics Biomarker Signatures in Precision Medicine. Int. J. Mol. Sci. 2019, 20, 4781.
  4. Sun, C.; Bernards, R. Feedback and redundancy in receptor tyrosine kinase signaling: Relevance to cancer therapies. Trends Biochem. Sci. 2014, 39, 465–474.
  5. Paccez, J.D.; Vogelsang, M.; Parker, M.I.; Zerbini, L.F. The receptor tyrosine kinase Axl in cancer: Biological functions and therapeutic implications. Int. J. Cancer 2014, 134, 1024–1033.
  6. Siveen, K.S.; Prabhu, K.S.; Achkar, I.W.; Kuttikrishnan, S.; Shyam, S.; Khan, A.Q.; Merhi, M.; Dermime, S.; Uddin, S. Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products. Mol. Cancer 2018, 17, 31.
  7. Meric, F.; Lee, W.P.; Sahin, A.; Zhang, H.; Kung, H.J.; Hung, M.C. Expression profile of tyrosine kinases in breast cancer. Clin. Cancer Res. 2002, 8, 361–367.
  8. Schenk, P.W.; Snaar-Jagalska, B.E. Signal perception and transduction: The role of protein kinases. Biochim. Biophys. Acta 1999, 1449, 1–24.
  9. Paul, M.K.; Mukhopadhyay, A.K. Tyrosine kinase—Role and significance in Cancer. Int. J. Med. Sci. 2004, 1, 101–115.
  10. Du, Z.; Lovly, C.M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer 2018, 17, 58.
  11. Li, Y.; Ye, X.; Tan, C.; Hongo, J.A.; Zha, J.; Liu, J.; Kallop, D.; Ludlam, M.J.; Pei, L. Axl as a potential therapeutic target in cancer: Role of Axl in tumor growth, metastasis and angiogenesis. Oncogene 2009, 28, 3442–3455.
  12. Verma, A.; Warner, S.L.; Vankayalapati, H.; Bearss, D.J.; Sharma, S. Targeting Axl and Mer kinases in cancer. Mol. Cancer 2011, 10, 1763–1773.
  13. Rankin, E.B.; Giaccia, A.J. The Receptor Tyrosine Kinase AXL in Cancer Progression. Cancers 2016, 8, 103.
  14. Hafizi, S.; Dahlback, B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 2006, 17, 295–304.
  15. Wu, X.; Liu, X.; Koul, S.; Lee, C.Y.; Zhang, Z.; Halmos, B. AXL kinase as a novel target for cancer therapy. Oncotarget 2014, 5, 9546–9563.
  16. Caberoy, N.B.; Alvarado, G.; Bigcas, J.L.; Li, W. Galectin-3 is a new MerTK-specific eat-me signal. J. Cell Physiol. 2012, 227, 401–407.
  17. Linger, R.M.; Keating, A.K.; Earp, H.S.; Graham, D.K. TAM receptor tyrosine kinases: Biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 2008, 100, 35–83.
  18. Graham, D.K.; DeRyckere, D.; Davies, K.D.; Earp, H.S. The TAM family: Phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer 2014, 14, 769–785.
  19. Xie, S.; Li, Y.; Li, X.; Wang, L.; Yang, N.; Wang, Y.; Wei, H. Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib. Oncotarget 2015, 6, 9206–9219.
  20. Chien, C.W.; Hou, P.C.; Wu, H.C.; Chang, Y.L.; Lin, S.C.; Lin, S.C.; Lin, B.W.; Lee, J.C.; Chang, Y.J.; Sun, H.S.; et al. Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer. Oncogene 2016, 35, 5872–5881.
  21. Antony, J.; Huang, R.Y. AXL-Driven EMT State as a Targetable Conduit in Cancer. Cancer Res. 2017, 77, 3725–3732.
  22. ClinicalTrials.gov. Available online: https://clinicaltrials.gov (accessed on 2 November 2020).
  23. Chen, F.; Song, Q.; Yu, Q. Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. Am. J. Cancer Res. 2018, 8, 1466–1482.
  24. Wilson, C.; Ye, X.; Pham, T.; Lin, E.; Chan, S.; McNamara, E.; Neve, R.M.; Belmont, L.; Koeppen, H.; Yauch, R.L.; et al. AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs. Cancer Res. 2014, 74, 5878–5890.
  25. Wang, C.; Jin, H.; Wang, N.; Fan, S.; Wang, Y.; Zhang, Y.; Wei, L.; Tao, X.; Gu, D.; Zhao, F.; et al. Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3beta/beta-catenin Signaling. Theranostics 2016, 6, 1205–1219.
  26. Holland, S.J.; Pan, A.; Franci, C.; Hu, Y.; Chang, B.; Li, W.; Duan, M.; Torneros, A.; Yu, J.; Heckrodt, T.J.; et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010, 70, 1544–1554.
  27. Lee, J.E.; Kwon, Y.J.; Baek, H.S.; Ye, D.J.; Cho, E.; Choi, H.K.; Oh, K.S.; Chun, Y.J. Synergistic induction of apoptosis by combination treatment with mesupron and auranofin in human breast cancer cells. Arch. Pharm. Res. 2017, 40, 746–759.
  28. Ryu, Y.S.; Shin, S.; An, H.G.; Kwon, T.U.; Baek, H.S.; Kwon, Y.J.; Chun, Y.J. Synergistic Induction of Apoptosis by the Combination of an Axl Inhibitor and Auranofin in Human Breast Cancer Cells. Biomol. Ther. 2020, 28, 473–481.
  29. Zhang, Y.X.; Knyazev, P.G.; Cheburkin, Y.V.; Sharma, K.; Knyazev, Y.P.; Orfi, L.; Szabadkai, I.; Daub, H.; Keri, G.; Ullrich, A. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008, 68, 1905–1915.
  30. Ye, X.; Li, Y.; Stawicki, S.; Couto, S.; Eastham-Anderson, J.; Kallop, D.; Weimer, R.; Wu, Y.; Pei, L. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene 2010, 29, 5254–5264.
  31. Cerchia, L.; Esposito, C.L.; Camorani, S.; Rienzo, A.; Stasio, L.; Insabato, L.; Affuso, A.; de Franciscis, V. Targeting Axl with an high-affinity inhibitory aptamer. Mol. Ther. 2012, 20, 2291–2303.
  32. Quirico, L.; Orso, F.; Esposito, C.L.; Bertone, S.; Coppo, R.; Conti, L.; Catuogno, S.; Cavallo, F.; de Franciscis, V.; Taverna, D. Axl-148b chimeric aptamers inhibit breast cancer and melanoma progression. Int. J. Biol. Sci. 2020, 16, 1238–1251.
  33. Ma, Z.; Yao, G.; Zhou, B.; Fan, Y.; Gao, S.; Feng, X. The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo. Mol. Med. Rep. 2012, 6, 897–903.
  34. Park, J.S.; Lee, C.; Kim, H.K.; Kim, D.; Son, J.B.; Ko, E.; Cho, J.H.; Kim, N.D.; Nan, H.Y.; Kim, C.Y.; et al. Suppression of the metastatic spread of breast cancer by DN10764 (AZD7762)-mediated inhibition of AXL signaling. Oncotarget 2016, 7, 83308–83318.
  35. Wang, X.; Saso, H.; Iwamoto, T.; Xia, W.; Gong, Y.; Pusztai, L.; Woodward, W.A.; Reuben, J.M.; Warner, S.L.; Bearss, D.J.; et al. TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase. Cancer Res. 2013, 73, 6516–6525.
  36. Shen, Y.; Chen, X.; He, J.; Liao, D.; Zu, X. Axl inhibitors as novel cancer therapeutic agents. Life Sci. 2018, 198, 99–111.
  37. Shen, Y.; Zhang, W.; Liu, J.; He, J.; Cao, R.; Chen, X.; Peng, X.; Xu, H.; Zhao, Q.; Zhong, J.; et al. Therapeutic activity of DCC-2036, a novel tyrosine kinase inhibitor, against triple-negative breast cancer patient-derived xenografts by targeting AXL/MET. Int. J. Cancer 2019, 144, 651–664.
  38. Okimoto, R.A.; Bivona, T.G. AXL receptor tyrosine kinase as a therapeutic target in NSCLC. Lung Cancer 2015, 6, 27–34.
  39. Iacovelli, R.; Ciccarese, C.; Fornarini, G.; Massari, F.; Bimbatti, D.; Mosillo, C.; Rebuzzi, S.E.; Di Nunno, V.; Grassi, M.; Fantinel, E.; et al. Cabozantinib-related cardiotoxicity: A prospective analysis in a “real world” cohort of metastatic renal cell carcinoma patients. Br. J. Clin. Pharm. 2019.
  40. Viola, D.; Elisei, R. Management of Medullary Thyroid Cancer. Endocrinol. Metab. Clin. N. Am. 2019, 48, 285–301.
  41. Nokihara, H.; Nishio, M.; Yamamoto, N.; Fujiwara, Y.; Horinouchi, H.; Kanda, S.; Horiike, A.; Ohyanagi, F.; Yanagitani, N.; Nguyen, L.; et al. Phase 1 Study of Cabozantinib in Japanese Patients With Expansion Cohorts in Non-Small-Cell Lung Cancer. Clin. Lung Cancer 2018.
  42. Tolaney, S.M.; Ziehr, D.R.; Guo, H.; Ng, M.R.; Barry, W.T.; Higgins, M.J.; Isakoff, S.J.; Brock, J.E.; Ivanova, E.V.; Paweletz, C.P.; et al. Phase II and Biomarker Study of Cabozantinib in Metastatic Triple-Negative Breast Cancer Patients. Oncologist 2017, 22, 25–32.
  43. Grullich, C. Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res. 2018, 211, 67–75.
  44. Liu, L.; Greger, J.; Shi, H.; Liu, Y.; Greshock, J.; Annan, R.; Halsey, W.; Sathe, G.M.; Martin, A.M.; Gilmer, T.M. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: Activation of AXL. Cancer Res. 2009, 69, 6871–6878.
  45. Kawada, I.; Hasina, R.; Arif, Q.; Mueller, J.; Smithberger, E.; Husain, A.N.; Vokes, E.E.; Salgia, R. Dramatic antitumor effects of the dual MET/RON small-molecule inhibitor LY2801653 in non-small cell lung cancer. Cancer Res. 2014, 74, 884–895.
  46. Konicek, B.W.; Capen, A.R.; Credille, K.M.; Ebert, P.J.; Falcon, B.L.; Heady, G.L.; Patel, B.K.R.; Peek, V.L.; Stephens, J.R.; Stewart, J.A.; et al. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget 2018, 9, 13796–13806.
  47. Kantarjian, H.M.; Cortes, J.E.; Kim, D.W.; Khoury, H.J.; Brummendorf, T.H.; Porkka, K.; Martinelli, G.; Durrant, S.; Leip, E.; Kelly, V.; et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 2014, 123, 1309–1318.
  48. Vultur, A.; Buettner, R.; Kowolik, C.; Liang, W.; Smith, D.; Boschelli, F.; Jove, R. SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol. Cancer 2008, 7, 1185–1194.
  49. Hebbard, L.; Cecena, G.; Golas, J.; Sawada, J.; Ellies, L.G.; Charbono, A.; Williams, R.; Jimenez, R.E.; Wankell, M.; Arndt, K.T.; et al. Control of mammary tumor differentiation by SKI-606 (bosutinib). Oncogene 2011, 30, 301–312.
  50. Zou, H.Y.; Li, Q.; Lee, J.H.; Arango, M.E.; McDonnell, S.R.; Yamazaki, S.; Koudriakova, T.B.; Alton, G.; Cui, J.J.; Kung, P.P.; et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007, 67, 4408–4417.
  51. Ayoub, N.M.; Al-Shami, K.M.; Alqudah, M.A.; Mhaidat, N.M. Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents. Onco Targets Ther. 2017, 10, 4869–4883.
  52. Rayson, D.; Lupichuk, S.; Potvin, K.; Dent, S.; Shenkier, T.; Dhesy-Thind, S.; Ellard, S.L.; Prady, C.; Salim, M.; Farmer, P.; et al. Canadian Cancer Trials Group IND197: A phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer. Breast Cancer Res. Treat. 2016, 157, 109–116.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Italia Falcone
,
Fabiana Conciatori
,
Chiara Bazzichetto
,
Emilio Bria
,
Luisa Carbognin
,
Paola Malaguti
,
Gianluigi Ferretti
,
Francesco Cognetti
,
Michele Milella
,
Ludovica Ciuffreda
View Times: 751
Revisions: 4 times (View History)
Update Date: 24 Nov 2020
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback