LSI Seminar Series: L1CAM is required for EGFR/ERK reactivation and persister survival in PDAC cells

KRAS-driven cancers adapt around targeted therapy, limited less by initial response than by drug-tolerant persister cells that seed recurrence. Using a Drosophila oncogenic-Ras screen, we identified Neuroglian, the fly ortholog of L1CAM, as a selective modifier of Ras-driven tumor overgrowth that acts through a cell-delamination-independent survival mechanism. This translated to human pancreatic cancer, where L1CAM is upregulated in oncogenic-Ras cells and its high expression concords with poor outcome. In PDAC models, L1CAM is required for EGFR and ERK reactivation following RAS-pathway inhibition, and its depletion sensitizes cells to EGFR inhibition and to the RAS(ON) inhibitor daraxonrasib (RMC-6236), with combined L1CAM loss plus KRASi/EGFRi nearly eliminating the residual persister population. This function is independent of STAT3, positioning L1CAM as a distinct, parallel survival axis. 

The speaker will explain these findings as well as immune-competent in vivo models now underway.