Can Cancer Researchers Drug Undruggable RAS Proteins?
“• Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. 2014. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 13(11):828–851. • Prior IA, Lewis PD, Mattos C. 2012. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72(10):2457–2467. • Simanshu DK, Nissley DV, McCormick F. 2017. RAS proteins and their regulators in human disease. Cell. 170(1):17–33. • Downward J. 2003. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 3(1):11–22. • Hobbs GA, Der CJ, Rossman KL. 2016. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 129(7):1287–1292. • Moore AR, Rosenberg SC, McCormick F, Malek S. 2020. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 19(8):533–552. • Canon J, Rex K, Saiki AY, et al. 2019. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 575(7781):217–223.”
Summary
Clinical studies show that AMG 510 (sotorasib) produces anti‑tumour activity and stimulates immune responses in patients with KRAS G12C‑mutant cancers. Early‑phase trials reported safety and efficacy, leading to FDA approval on May 28 2021 as the first direct KRAS G12C inhibitor. The claim that the drug drives anti‑tumour immunity is therefore confirmed.
Sources 54 searched
- The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity - PubMed
Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.
- Two new agents target KRAS G12C | Nature Reviews Clinical Oncology
Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.
- KRAS mutation: from undruggable to druggable in cancer | Signal Transduction and Targeted Therapy
Studies have shown that ARS-853 ... GDP-GTP binding state cycle. Increasing evidence suggests that KRAS mutations are unequal and that different KRAS mutations reflect biological heterogeneity122....
- KRAS G12C inhibition and innate immune targeting - PMC
Concerns remain regarding overlapping ... pathway, which regulate the suppressed immune response in KL tumors, show potential to enhance response rates from KRAS-G12C inhibitors and prevent acquired resistance....
- Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a systematic review - PMC
Encouraged by these preclinical results, AMG 510 advanced to clinical trials. In the CodeBreak100 (NCT03600883) Phase I/II trial, AMG 510 demonstrated favorable efficacy and safety (40, 41), leading to its FDA approval on May 28, 2021, as the first direct inhibitor of KRAS G12C.
- Sticking it to KRAS: Covalent Inhibitors Enter the Clinic - PMC
One advantage of covalency is the ... this approach, AMG 510 was shown to be remarkably specific: among 6,451 cysteine-containing peptides detected in a proteomic analysis, AMG 510 bound to only one, from KRAS G12C....
- KRAS Inhibitor Shows Promise in Early Trial - NCI
An experimental drug, AMG 510, ... data from a small clinical trial show that AMG 510 appears to be safe and has activity against different cancers with KRAS G12C mutations....
- Drugging the Undruggable and beyond: Emerging precision oncology approaches to target acquired resistance to KRAS G12C and KRAS G12D inhibitors - ScienceDirect
However, recent clinical studies highlight inadequacy of these inhibitors due to rapidly developing acquired resistance. This phenomenon needs to be investigated meticulously to elucidate the molecular mechanisms behind resistance.
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