January 1, 2020
Two days after seeding, organoids were 605 treated with ERKi SCH772984 (0 nM to 10 ÎźM) or MEKi AZD6244 (selumetinib) (0 to 2.5 ÎźM), randomized on a Tecan D300e drug dispenser. O
Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (âź1%) in lung and colorectal cancers, yet relatively common (âź20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110Îą PI3K (PI3KÎą), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3KÎł activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRASG12R is impaired in activating a key effector, p110Îą PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3KÎł in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.See related commentary by FalcomatĂ et al., p. 23.This article is highlighted in the In This Issue feature, p. 1. Š2019 American Association for Cancer Research.
Hobbs, GA; Baker, NM; Miermont, AM; Thurman, RD; Pierobon, M; Tran, TH; Anderson, AO; Waters, AM; Diehl, JN; Papke, B; Hodge, RG; Klomp, JE; Goodwin, CM; DeLiberty, JM; Wang, J; Ng, RWS; Gautam, P; Bryant, KL; Esposito, D; Campbell, SL; Petricoin, EF; Simanshu, DK; Aguirre, AJ; Wolpin, BM; Wennerberg, K; Rudloff, U; Cox, AD; Der, CJ;
Journal: Cancer Discov Pages: 104-123