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EGFR Blockade Reverts Resistance to KRAS^G12C Inhibition in Colorectal Cancer.

ABSTRACT: Most patients with KRAS ^G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS^G12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRAS^G12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS ^G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS ^G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRAS^G12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRAS^G12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRAS^G12C inhibitors. The combinatorial targeting of EGFR and KRAS^G12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS ^G12C colorectal cancer. SIGNIFICANCE: The efficacy of KRAS^G12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRAS^G12C inhibition in colorectal cancer. EGFR and KRAS^G12C should be concomitantly inhibited to overcome resistance to KRAS^G12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079.

SUBMITTER: Amodio V

PROVIDER: S-EPMC7416460 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer.

Amodio Vito V Yaeger Rona R Arcella Pamela P Cancelliere Carlotta C Lamba Simona S Lorenzato Annalisa A Arena Sabrina S Montone Monica M Mussolin Benedetta B Bian Yu Y Whaley Adele A Pinnelli Marika M Murciano-Goroff Yonina R YR Vakiani Efsevia E Valeri Nicola N Liao Wei-Li WL Bhalkikar Anuja A Thyparambil Sheeno S Zhao Hui-Yong HY de Stanchina Elisa E Marsoni Silvia S Siena Salvatore S Bertotti Andrea A Trusolino Livio L Li Bob T BT Rosen Neal N Di Nicolantonio Federica F Bardelli Alberto A Misale Sandra S

Cancer discovery 20200519 8

Most patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS G12C c ...[more]

PMID: 32430388

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Project description:BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

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EGFR Blockade Reverts Resistance to KRAS^G12C Inhibition in Colorectal Cancer.

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EGFR Blockade Reverts Resistance to KRAS<sup>G12C</sup> Inhibition in Colorectal Cancer.

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