Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition.

Yihsuan S Tsai,Joel S Parker,Benjamin G Vincent,Mark G Woodcock,Krishna L Kanchi,Salma H Azam,Leigh B Thorne,Chad V Pecot

doi:10.1172/jci155523

Abstract

BACKGROUNDThe KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed, they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance.METHODSHere, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep-RNA and whole-exome sequencing comparing pretreatment, posttreatment, and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition.RESULTSIn addition to decreased KRAS G12C–mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell–intrinsic and non–cell autonomous mechanisms included increased complement activation, coagulation, and tumor angiogenesis, and several lines of evidence of immunologic evasion.CONCLUSIONTogether, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling, and diverse remodeling of the tumor microenvironment.FUNDINGRichard and Fran Duley, Jimmy and Kay Mann, the NIH, and the North Carolina Biotechnology Center.

Highlights

Activated, mutant KRAS continuously stimulates downstream effector signaling and promotes most cancer hallmarks [1]
Using deep-RNA and whole-exome sequencing (WES) of pre- and post-AMG510-treatment samples, we reveal diverse clonal populations that occurred through altered cell-intrinsic, tumor-microenvironment (TME), and immunologic remodeling mechanisms of resistance
A 77-year-old male patient with prior smoking history was diagnosed with metastatic KRASG12C-mutant lung adenocarcinoma and 80% expression of programmed death ligand 1 (PD-L1)

Summary

Introduction

Activated, mutant KRAS continuously stimulates downstream effector signaling and promotes most cancer hallmarks [1]. Hotspot mutations that predominately occur in codons 12 and 13 result in defective KRAS GTPase activity, locking it into an active GTP-bound state. A remarkable breakthrough occurred when covalent allosteric inhibitors were discovered that could bind the cysteine residue within the switch II region of the KRAS G12C mutation, locking the protein in its inac-. More potent KRAS G12C inhibitors rapidly emerged, and recently expanded phase I trials with sotorasib (AMG510) and adagrasib (MRTX849) have demonstrated tumor response rates of approximately 30% to 40% in lung cancer and a safe toxicity profile [4,5,6]. We present a KRASG12C-mutant lung adenocarcinoma patient who initially responded to AMG510 but rapidly developed numerous mechanisms of resistance. Allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. They are often short-lived, making in-depth characterization of the mechanisms of resistance of paramount importance

Methods

Results

Conclusion