Drugging KRAS: current perspectives and state-of-art review

Abstract

After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the ‘holy grail’ of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound ‘off’ state and the GTP-bound ‘on’ state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.

RAS‐targeted cancer therapy: Advances in drugging specific mutations

“…Adagrasib is also being studied in CRC with KRAS G12C 123 . With a median follow‐up of 12.8 months, the response rate among patients was 22%, with a disease control rate of 87%, and the mPFS was 5.6 months.…”

Selected Approaches to Disrupting Protein–Protein Interactions within the MAPK/RAS Pathway

“…X-ray crystal structures show that even when in the GTP-bound state, the Switch-II loop is perturbed and is not competent to bind RAF ( Figure 11 B). There are currently numerous reviews [ 35 , 113 , 114 , 115 ] on the topic of KRAS Switch-II pocket binders; thus, we will forego a compound-by-compound dissection of this subject matter.…”

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor

“…Despite being well recognized in malignant cancer, various attempts to inhibit mutant KRAS in the past have failed. KRAS has long been considered to be an undruggable target, until recently when several small molecules have been developed that specifically target KRAS G12C . , AMG510 (sotorasib), the first approved KRAS G12C inhibitor, selectively binds KRAS G12C to lock it in its inactive conformation and has shown promising efficacy in patients with NSCLC and colorectal cancer. ,, However, the overall response rate (ORR) for AMG510 treatment of NSCLC patients with the KRAS G12C mutation was 36%, which was lower than that of NSCLC patients treated with osimertinib or alectinib. − The diverse genomic and histologic mechanisms conferring insensitivity to AMG510 . Novel therapeutic strategies or combination therapy intensive efforts are underway to improve the antitumor response to KRAS G12C inhibition therapy …”

“…KRAS has long been considered to be an undruggable target, until recently when several small molecules have been developed that specifically target KRAS G12C . 4,5 AMG510 (sotorasib), the first approved KRAS G12C inhibitor, selectively binds KRAS G12C to lock it in its inactive conformation and has shown promising efficacy in patients with NSCLC and colorectal cancer. 4,6,7 However, the overall response rate (ORR) for AMG510 treatment of NSCLC patients with the KRAS G12C mutation was 36%, which was lower than that of NSCLC patients treated with osimertinib or alectinib.…”

“…4,5 AMG510 (sotorasib), the first approved KRAS G12C inhibitor, selectively binds KRAS G12C to lock it in its inactive conformation and has shown promising efficacy in patients with NSCLC and colorectal cancer. 4,6,7 However, the overall response rate (ORR) for AMG510 treatment of NSCLC patients with the KRAS G12C mutation was 36%, which was lower than that of NSCLC patients treated with osimertinib or alectinib. 8−10 The diverse genomic and histologic mechanisms conferring insensitivity to AMG510.…”