Journal
CANCER DISCOVERY
Volume 10, Issue 8, Pages 1129-1139Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0187
Keywords
-
Categories
Funding
- AIRC, Associazione Italiana per la Ricerca sul Cancro [20697, 21407, 22802]
- AIRC under 5 per Mille 2018 program [21091]
- European Research Council [724748 -BEAT, 754923 COLOSSUS, 731105 EDIReX]
- AIRC/CRUK/FC AECC Accelerator Award [22795]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, 5 x 1000 Ministero della Salute 2015 Project STRATEGY
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS
- 5 x 1000 Ministero della Salute 2015 Project IMMUNOGENOMICA
- AIRC MFAG 2017 [20236]
- NIH [R01 CA233736]
- Cancer Center Core Grant [P30 CA008748]
- AIRC IG 2018 [21923]
- 5 x 1000 Ministero della Salute 2014
- 5 x 1000 Ministero della Salute 2016
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available