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
Ren-Wang Peng
 + 1337 word(s) 1337 2022-01-17 09:21:29 |
2 corrected the format
Dean Liu
 Meta information modification 1337 2022-01-19 01:31:52 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Peng, R. A Breakthrough Brought about by Targeting KRASG12C. Encyclopedia. Available online: https://encyclopedia.pub/entry/18407 (accessed on 01 July 2024).
Peng R. A Breakthrough Brought about by Targeting KRASG12C. Encyclopedia. Available at: https://encyclopedia.pub/entry/18407. Accessed July 01, 2024.
Peng, Ren-Wang. "A Breakthrough Brought about by Targeting KRASG12C" Encyclopedia, https://encyclopedia.pub/entry/18407 (accessed July 01, 2024).
Peng, R. (2022, January 18). A Breakthrough Brought about by Targeting KRASG12C. In Encyclopedia. https://encyclopedia.pub/entry/18407
Peng, Ren-Wang. "A Breakthrough Brought about by Targeting KRASG12C." Encyclopedia. Web. 18 January, 2022.
A Breakthrough Brought about by Targeting KRASG12C
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers14020390

KRAS is the most frequently mutated member of the RAS family, present in 96% of pancreatic ductal adenocarcinoma (PDAC), 52% of colorectal, 32% of lung carcinomas, and to a lesser extent in a variety of other cancers, with alterations mostly occurring at codon G12, G13, and Q61.

 

KRAS-mutant cancer KRASG12C KRASG12C inhibitors acquired resistance combination therapy

1. Challenges in Therapeutic Targeting of KRAS

The tractability of RAS as a drug target has been significantly confounded for several reasons. First, given the high affinity of GDP-KRAS complexes for GTPs and the abundance of cellular GTPs, it is technically difficult to interfere with the GDP–GTP exchange using GTP analogs that compete for GTP binding [1][2]. The strategy to prevent GTP-KRAS formation by interfering with the interaction with GEFs also failed, as the inhibition affects both KRAS wild-type and mutant cells [3][4]. Finally, RAS proteins lack known allosteric regulation sites, which has thwarted efforts to develop allosteric inhibitors.
Meanwhile, it has been noticed that the surface formation of RAS is highly flexible [3][5]. Based on this observation, recent attempts have been made to identify new binding sites/grooves on the surface of KRAS, which was previously regarded as smooth, and to develop selective inhibitors that bind to the groove.

2. G12C Mutation: A Tale of Drugging the Undruggable

The discovery of an ideal groove on the smooth surface of the KRAS protein seemed to be an impossible mission until 2013, when it was shown that the switch-II pocket (S-IIP) is potentially targetable when KRAS proteins have the G12C substitution [6].
In an attempt to overcome the challenges of inhibiting RAS directly, Shokat and co-workers explored a novel approach to covalently target the reactive cysteine-12 of KRASG12C, which is located in close proximity to both the nucleotide pocket and a previously unrecognized surface groove in the switch-II region (S-IIP). Interestingly, the covalent modification of the mutant C12 only occurs in GDP-bound KRAS, as S-IIP is absent in GTP-bound KRAS [7][6]. The formation of an irreversible and covalent bond between the inhibitor and the cysteine residue of KRASG12C irreversibly disrupts both switch-I and switch-II, reduces the affinity of KRAS for guanosine nucleotides despite the presence of GTP, and allows for the persistent disruption of the adducted protein, which locks KRASG12C in the GDP-bound conformation. Notably, these inhibitors rely on the intrinsic GTPase of mutant KRASG12C, i.e., the KRASG12C protein is still able to alternate between their active and inactive state, as GTP-bound KRAS is the predominant form in KRASG12C-mutant cancer cells. Such a mutant-specific strategy enables the selective inhibition of KRASG12C while sparing the other KRAS mutants (e.g., G12D, G12S, G12S, G13D, Q61H, etc.) or KRAS wild-type cells (e.g., normal tissue), potentially overcoming the toxicological challenges elicited by the nonselective inhibition of KRAS-driven cell growth [6].
ARS853. The first G12C-selective inhibitor was developed based on the so-called compound 12, which is described as the most potent candidate in the primary report. ARS853 covalently binds to cysteine residue 12 with high affinity and can signficantly affect the active KRAS protein as well as its downstream effectors, such as the RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways, by inducing apoptosis and decreasing cell proliferation in vitro [8][9]. The high selectivity of ARS853 has also been demonstrated by the fact that its inhibitory effects can be abrogated by the ectopic expression of KRASG12C substitution [9].
ARS1620. Compared to ARS853, which was successful in in vitro studies, the second-generation inhibitor ARS1620 has improved pharmacological properties (e.g., metabolic stability), making it the first inhibitor with in vivo efficacy [10]. ARS1620 was not only optimized for in vivo stability, but also exhibited an intensive potency in G12C occupation and the effective blockade of RAS signaling [11]. In a Mia.paca-2 cell line xenograft, tumor growth was completely inhibited at a drug dose of 200 mg/kg, and the protein levels of RAS-GTP, phospho-ERK, phospho-AKT, and phospho-S6 were all significantly downregulated. In comparison, ARS1620 shows no effects in KRASG12V mutant xenografts.
AMG510 (sotorasib). Derived from ARS1620, this third-generation sotorasib is the first G12C inhibitor to enter and complete clinical trials. Based on the promising results of the NCT03600883 trial and an ongoing phase III clinical trial (CodeBreaK 200; https://doi.org/10.1016/j.jtho.2020.10.137 accessed on 21 November 2021), AMG510 was recently approved by the FDA (the United States Food and Drug Administration) for the treatment of locally advanced or metastatic NSCLC [12][13]. Compared to ARS853 and ARS1620, a breakthrough of AMG510 is that its binding induces an alternative orientation of histidine 95 (His-95), which provides a novel surface groove on KRASG12C that can be occupied by the aromatic rings of AMG510, leading to the enhanced interaction of AMG510 with KRASG12C via van der Waals contacts and the improved potency of AMG510. Indeed, AMG510 exhibits a 10-fold increase in efficacy and improved kinetics compared to ARS1620. The onset of the maximal inhibition of the MAPK pathway occurs 2–4 h after exposure to AMG510, which maintains the inhibition of phospho-ERK in vivo for up to 48 h [12].
The safety and tolerability profile of AMG510 was demonstrated in a phase I study [14] that included 59 cases of NSCLC, 42 cases of colorectal cancer, and 28 cases of other tumors. The total 129 patients were divided into four cohorts with planned doses of 180, 360, 720, and 960 mg per day, respectively. The mean elimination half-life of the drug was 5.5 h. Treatment-related adverse effects occurred in 73 patients (56.58%), of which 15 patients had grade 3 or 4 effects, e.g., an increase in alanine aminotransferase (ALT), diarrhea, anemia, an increase in aspartate aminotransferase (AST), an increase in blood alkaline phosphatase, hepatitis, a decrease in lymphocyte count, an increase in γ-glutamyltransferase, and hyponatremia. The treatment showed high potential anticancer activity, especially in the subgroup of NSCLC: 19 patients had a confirmed partial response and 33 had stable disease. That is, the confirmed response rate was 32.2% and disease control (including objective response and stable disease) was 88.1%. In this subgroup, the median progression-free survival was 6.3 months. In addition, 34 patients with NSCLC in the 960 mg cohort had a more satisfactory disease control rate of 91.2%.
In a phase II study of 126 NSCLC patients, the efficacy of sotorasib was further evaluated [15]. While complete responses were observed in four cases only, a partial response occurred in 42 cases and stable disease in 54 cases. Although the reported overall objective response rate was 37.1% and the disease control rate was 80.6%, the median progression-free survival (PFS) was 6.8 months. Treatment-related adverse events (TRAEs) were observed in 69.8% of patients, with 20.6% of patients experiencing severe TRAEs (twenty-five grade 3 events and one grade 4 event).
MRTX849 (adagrasib). MRTX849 is another third-generation drug for targeting KRASG12C that may well receive final approval. MRTX849 has a relatively long half-life of 17 to 48 h [16][17], and its efficacy in discriminating KRASG12C activity was widely confirmed in KRASG12C-mutant cell lines under both 2D and 3D conditions. On the contrary, non-KRASG12C-mutant cell lines showed IC50 values greater than 1 μM in 2D and greater than 3 μM under 3D conditions [16]. An RNA sequencing analysis of a xenograft mouse model confirmed that ERK-dependent transcription was blocked, accompanied by the reactivation of receptor tyrosine kinase (RTK)- and ERK-dependent signaling.
Based on these in vitro and in vivo data, a phase I/II clinical trial (NCT03785249) was then conducted. Adagrasib is also well tolerated and provides great benefits to patients with KRASG12C-mutant cancers [18][19]. In 110 patients with colorectal cancer or NSCLC, treatment-relative adverse events occurred in 85% of cases, including 33 patients with grade 3 or 4 adverse events. Clinical activity was evaluable in 51 patients, of whom 23 patients had a partial response and 26 patients had stable disease. Overall, the disease control rate was up to 96%. In addition, an objective response rate of 43% was confirmed in 14 phaseI/Ib patients with a longer follow-up.
Other G12C inhibitors. GDC-6036, JNJ-74699157 (ARS-3248), and LY3499446 are other inhibitors in the field. The latter two candidates have been enrolled in clinical trials without much reporting of preclinical evidence. The clinical trial of JNJ-74699157 (NCT04006301) was reported to be completed after less than a year, with only 10 participants recruited and no result published. The study of LY3499446 (NCT04165031) was terminated at the end of 2020 due to an unexpected toxicity finding.

References

  1. Becher, I.; Savitski, M.M.; Savitski, M.F.; Hopf, C.; Bantscheff, M.; Drewes, G. Affinity profiling of the cellular kinome for the nucleotide cofactors ATP, ADP, and GTP. ACS Chem. Biol. 2013, 8, 599–607.
  2. Noonan, T.; Brown, N.; Dudycz, L.; Wright, G. Interaction of GTP derivatives with cellular and oncogenic ras-p21 proteins. J. Med. Chem. 1991, 34, 1302–1307.
  3. Maurer, T.; Garrenton, L.S.; Oh, A.; Pitts, K.; Anderson, D.J.; Skelton, N.J.; Fauber, B.P.; Pan, B.; Malek, S.; Stokoe, D.; et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl. Acad. Sci. USA 2012, 109, 5299–5304.
  4. Hillig, R.C.; Sautier, B.; Schroeder, J.; Moosmayer, D.; Hilpmann, A.; Stegmann, C.M.; Werbeck, N.D.; Briem, H.; Boemer, U.; Weiske, J.; et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction. Proc. Natl. Acad. Sci. USA 2019, 116, 2551–2560.
  5. Pantsar, T. The current understanding of KRAS protein structure and dynamics. Comput. Struct. Biotechnol. J. 2020, 18, 189–198.
  6. Ostrem, J.M.; Peters, U.; Sos, M.L.; Wells, J.A.; Shokat, K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013, 503, 548–551.
  7. Chen, H.; Smaill, J.B.; Liu, T.; Ding, K.; Lu, X. Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics. J. Med. Chem. 2020, 63, 14404–14424.
  8. Lito, P.; Solomon, M.; Li, L.S.; Hansen, R.; Rosen, N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 2016, 351, 604–608.
  9. Patricelli, M.P.; Janes, M.R.; Li, L.S.; Hansen, R.; Peters, U.; Kessler, L.V.; Chen, Y.; Kucharski, J.M.; Feng, J.; Ely, T.; et al. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov. 2016, 6, 316–329.
  10. Dunnett-Kane, V.; Nicola, P.; Blackhall, F.; Lindsay, C. Mechanisms of Resistance to KRAS(G12C) Inhibitors. Cancers 2021, 13, 151.
  11. Janes, M.R.; Zhang, J.; Li, L.S.; Hansen, R.; Peters, U.; Guo, X.; Chen, Y.; Babbar, A.; Firdaus, S.J.; Darjania, L.; et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell 2018, 172, 578–589.e17.
  12. Canon, J.; Rex, K.; Saiki, A.Y.; Mohr, C.; Cooke, K.; Bagal, D.; Gaida, K.; Holt, T.; Knutson, C.G.; Koppada, N.; et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019, 575, 217–223.
  13. Blair, H.A. Sotorasib: First Approval. Drugs 2021, 81, 1573–1579.
  14. Hong, D.S.; Fakih, M.G.; Strickler, J.H.; Desai, J.; Durm, G.A.; Shapiro, G.I.; Falchook, G.S.; Price, T.J.; Sacher, A.; Denlinger, C.S.; et al. KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N. Engl. J. Med. 2020, 383, 1207–1217.
  15. Skoulidis, F.; Fakih, M.G.; Strickler, J.H.; Desai, J.; Durm, G.A.; Shapiro, G.I.; Falchook, G.S.; Price, T.J.; Sacher, A.; Denlinger, C.S.; et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N. Engl. J. Med. 2021, 384, 2371–2381.
  16. Hallin, J.; Engstrom, L.D.; Hargis, L.; Calinisan, A.; Aranda, R.; Briere, D.M.; Sudhakar, N.; Bowcut, V.; Baer, B.R.; Ballard, J.A.; et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020, 10, 54–71.
  17. Fell, J.B.; Fischer, J.P.; Baer, B.R.; Blake, J.F.; Bouhana, K.; Briere, D.M.; Brown, K.D.; Burgess, L.E.; Burns, A.C.; Burkard, M.R.; et al. Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer. J. Med. Chem. 2020, 63, 6679–6693.
  18. Jänne, P.; Rybkin, I.I.; Spira, A.I.; Riely, G.J.; Papadopoulos, K.P.; Sabari, J.K.; Johnson, M.L.; Heist, R.S.; Bazhenova, L.; Barve, M.; et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur. J. Cancer 2020, 138, S1–S2.
  19. Johnson, M.L.; Ou, S.H.I.; Barve, M.; Rybkin, I.I.; Papadopoulos, K.P.; Leal, T.A.; Velastegui, K.; Christensen, J.G.; Kheoh, T.; Chao, R.C.; et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with colorectal cancer (CRC) and other solid tumors harboring a KRAS G12C mutation. EJC 2020, 138, S1–S2.
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
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ren-Wang Peng
View Times: 484
Revisions: 2 times (View History)
Update Date: 19 Jan 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback