EGFR blockade reverts resistance to KRAS(G12C) inhibition in colorectal cancer Journal Article
| Authors: | Amodio, V.; Yaeger, R.; Arcella, P.; Cancelliere, C.; Lamba, S.; Lorenzato, A.; Arena, S.; Montone, M.; Mussolin, B.; Bian, Y.; Whaley, A.; Pinnelli, M.; Murciano-Goroff, Y. R.; Vakiani, E.; Valeri, N.; Liao, W. L.; Bhalkikar, A.; Thyparambil, S.; Zhao, H. Y.; de Stanchina, E.; Marsoni, S.; Siena, S.; Bertotti, A.; Trusolino, L.; Li, B. T.; Rosen, N.; Di Nicolantonio, F.; Bardelli, A.; Misale, S. |
| Article Title: | 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. |
| Keywords: | cetuximab; ras; trial; acquired-resistance; landscape |
| Journal Title: | Cancer Discovery |
| Volume: | 10 |
| Issue: | 8 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-08-01 |
| Start Page: | 1129 |
| End Page: | 1139 |
| Language: | English |
| ACCESSION: | WOS:000558688700022 |
| DOI: | 10.1158/2159-8290.Cd-20-0187 |
| PROVIDER: | wos |
| PMCID: | PMC7416460 |
| PUBMED: | 32430388 |
| Notes: | Article -- Source: Wos |
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