Targeting RAF Kinases to Overcome Adaptive Resistance to RAS Targeted Therapies
Time: 9:00 am
day: Day Two
- Clinical and pre-clinical data emphasizes the frequency of on-target and onpathway (ERK-MAPK) adaptive and acquired resistance mechanisms to KRASG12C targeted therapies.
- CRISPR LoF screens in KRAS-G12C inhibitor resistant cell lines reveal gene subsets whose depletion restores sensitivity to KRASG12C inhibitor treatment. RAF kinases, notably CRAF, was uncovered as one such gene.
- CRISPR genetic ablation and acute protein destruction methods, including DTAG, provide unique insights into the kinetics of ERK-MAPK pathway modulation by CRAF. These technologies reveal mechanism of action hypotheses and biomarker opportunities for this challenging onco-target.