MSK KRASG12C Colorectal Resistance 2022

Overview

A clinical/translational dataset from Memorial Sloan Kettering Cancer Center characterizing the genetic mechanisms of acquired resistance to combined KRASG12C and EGFR inhibition in KRASG12C-mutant colorectal cancer (CRC). The dataset includes serial ctDNA from 12 patients treated with sotorasib or adagrasib plus anti-EGFR antibodies (cetuximab or panitumumab), as well as cell line and patient-derived xenograft (PDX) models of resistance.

Composition

  • 12 patients with KRASG12C-mutant colorectal cancer treated with combination KRASG12C + EGFR inhibition: adagrasib plus cetuximab (n = 8) or sotorasib plus panitumumab (n = 4).
  • Serial ctDNA collected approximately every 6 weeks in 4 patients for longitudinal resistance dynamics.
  • 2 KRASG12C-mutant CRC cell lines (C106, RW7213) grown to resistance in sotorasib plus cetuximab.
  • 1 KRASG12C-mutant CRC patient-derived xenograft (CLR113) treated with sotorasib plus cetuximab until acquired resistance.
  • Cancer type: colorectal adenocarcinoma (COADREAD).

Assays / panels (linked)

  • MSK-IMPACT (cell lines, PDX, tissue)
  • Guardant360 CDx (patients 1–5, 11)
  • ctDx FIRST (patients 6–10)
  • MSK-ACCESS (patient 12)

Papers using this cohort

  • PMID:36355783 — Characterization of acquired resistance to combined KRASG12C + EGFR inhibition in KRASG12C-mutant CRC; dataset is the primary source.

Notable findings derived from this cohort

  • Resistance to combined KRASG12C + EGFR inhibition was heterogeneous, with multiple low-frequency alterations co-occurring: RAS mutations (58.3%), MAPK pathway (58.3%), RTK activation (75%), PI3K-mTOR (25%), nuclear function (41.7%) PMID:36355783.
  • KRASG12C amplification (>20 copies) was identified as the only recurrent resistance alteration that increased steadily in proportion to tumor markers across patients; all other resistance alterations appeared and disappeared at low VAF PMID:36355783.
  • Drug withdrawal induced oncogene-induced senescence in KRASG12C-amplified resistant cells, creating a therapeutic vulnerability to the mTOR-targeting senolytic AZD8055, as validated in patient 12 tissue biopsy showing elevated p16 (2+, 65% cells vs. 5% pretreatment) and p-S6 PMID:36355783.

Sources

  • cBioPortal study: coadread_mskresistance_2022

This page was processed by crosslinker on 2026-05-06.