Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg

Abstract

Kirsten rat sarcoma viral oncogene homolog mutations are observed in 25% of lung adenocarcinoma and 40% of these are G12C mutations. Historically, no approved targeted agents were available for patients with any KRAS mutation, and response rates to standard-of-care therapies were suboptimal. Newly developed inhibitors directed toward KRAS^G12C have been successful in clinical trials with overall response rates ranging between 32% and 46%, and two FDA approvals were granted in May 2021 and December 2022 as second-line or later monotherapies. However, rapid tumor resistance complicates their use as a monotherapy. With the rapid development of this novel class of inhibitors, it is important to discern the different types of tumor resistance that may arise and how each can differently contribute to tumor growth and survival. G12C inhibitor resistance is under investigation and combinations of therapies with G12C inhibitors have been proposed. Much of this insight is gleaned from preclinical investigations, as our knowledge of clinical resistance is in its infancy. In this review, we summarize the preclinical development of KRAS^G12C inhibitors, their clinical evaluations, different types of resistance mechanisms to these compounds, and ways of overcoming them. Finally, we underscore the importance of basic and translational investigations of these molecules in a landscape where their clinical evaluations garner the most attention, and we set the stage for what is to come.

Keywords: G12C; KRAS; clinical trial; drug resistance; preclinical; targeted therapy.

Figure 1.

KRASWT complexed with GDP (PDB: 4OBE). (a) Allosteric and effector domains denoted by either purple or yellow colors, respectively. (b) Switch-I and Switch-II regions are colored cyan and orange, respectively. The red highlighted residue is G12. Switch-I is residues 30–38 inclusive while switch-II was considered residues 59–72 inclusive. Images were generated using PyMol version 2.5.2.

Figure 2.

Binding of different inhibitors on KRASG12C. (a) Molecular structure of sotorasib, adagrasib, and JDQ443. (b) Two different angles of aligned GDP with aligned sotorasib, adagrasib, and JDQ443 on KRASG12C. (c) Illustration of how different KRAS-G12Ci binding impacts KRAS protein conformation. (d) Two different angles of sotorasib, adagrasib, and JDQ443 binding on GDP-KRASG12C with several key KRAS residues highlighted. AMG 510 (PDB: 6OIM); MRTX849 (PDB: 6UT0); JDQ443 (PDB: 7R0M). Images were generated using PyMol version 2.5.2.

Figure 3.

Detailed schematic of adaptive and acquired GDP-KRASG12C inhibitor resistance. The MAPK and PI3K/AKT pathways are shown here. Any protein in green indicates mRNA or protein upregulation after GDP-KRASG12C inhibitor (G12Ci) treatment, while any protein in red indicates any secondary mutation or copy number amplification that occurred after G12Ci treatment. Clinical trials investigating G12Ci combination therapies with targeted molecules against specific proteins are listed here. This schematic fails to address the resistance mechanisms including but not limited to histologic transformation, genetic rearrangements, immunomodulation, or global proteome changes in metabolic programming.