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EML4-ALK Mediates Resistance to KRASG12C Inhibition and Induces an Oncogenic Dependency by Rewiring Signaling through the Wild-Type RAS Pathway.
Cancer Discovery · · Journal Article
Scaparone, Mira + more
Abstract ↗AI summary
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In KRASG12C-driven lung adenocarcinoma models with acquired EML4-ALK fusion, EML4-ALK rewires signaling to activate wild-type RAS and bypass KRASG12C inhibition.
- Why it matters: Limited clinical responses to KRASG12C-selective inhibitors and resistance via acquired genomic alterations leave a mechanistic gap for overcoming EML4-ALK–linked escape.
- What they did: The study examined resistant KRASG12C/EML4-ALK tumor cells and tested combined ALK/KRASG12C inhibition, plus sequential pressure with KRASG12C inhibitors followed by single-agent ALK inhibitors.
- The result: Combined ALK/KRASG12C inhibition is effective, and KRASG12C-inhibitor–pressured cells show sensitivity to single-agent ALK inhibitors, implying sequential ALK targeting and multi-selective RAS inhibitor opportunities.
The findingWhy it mattersWhat they didThe result
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