Adrian L. Gill, Mathew A. Marx
RAS Drug Discovery Past, Present and Future 2025, 205-227
https://doi.org/10.1016/B978-0-443-21861-3.00017-6
Krazati (adagrasib/MRTX849) is a potent, selective, and covalent KRASG12C inhibitor, representing a significant breakthrough in directly targeting KRAS. Adagrasib demonstrates favorable drug-like properties, selectively modifying mutant cysteine 12 in GDP-bound KRASG12C, leading to the inhibition of KRAS-dependent signaling both in vitro and in vivo, and tumor regression in many KRASG12C-positive cell lines and patient-derived xenograft models across various tumor types. Objective responses have been observed in clinical trials, particularly in lung and colon adenocarcinoma patients with KRASG12C mutations. Comprehensive pharmacodynamic and pharmacogenomic profiling in both sensitive and partially resistant nonclinical models has shed light on the mechanisms limiting adagrasib antitumor activity. These resistance mechanisms include contributing factors related to KRAS nucleotide cycling, feedback reactivation pathways through activation of receptor tyrosine kinases, instances where tumors bypass KRAS dependence, and genetic dysregulation of the cell cycle. The ongoing characterization of adagrasib's activity, along with insights into response and resistance mechanisms, provides valuable understanding of KRAS dependence and opened a long-awaited opportunity to selectively target KRASG12C in patients. Furthermore, the identification of effective preclinical combinations, such as adagrasib with agents targeting RTKs, SHP2, mTOR, or the cell cycle, demonstrates enhanced responses and marked tumor regression. These findings contribute to the rational development of this class of agents, holding promise for improving therapeutic outcomes in KRASG12C-mutant human cancers.
