Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer

G. Aaron Hobbs, Nicole M. Baker, Anne M. Miermont, Ryan D. Thurman, Mariaelena Pierobon, Timothy H. Tran, Andrew O. Anderson, Andrew M. Waters, J. Nathaniel Diehl, Bjoern Papke, Richard G. Hodge, Jennifer E. Klomp, Craig M. Goodwin, Jonathan M. DeLiberty, Junning Wang, Raymond W.S. Ng, Prson Gautam, Kirsten L. Bryant, Dominic Esposito, Sharon L. CampbellEmanuel F. Petricoin, Dhirendra K. Simanshu, Andrew J. Aguirre, Brian M. Wolpin, Krister Wennerberg, Udo Rudloff*, Adrienne D. Cox, Channing J. Der

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

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 (~1%) in lung and colorectal cancers, yet relatively common (~20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specifi c 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, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ 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, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this defi ciency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.

Original languageEnglish
Pages (from-to)104-123
Number of pages20
JournalCancer Discovery
Volume10
Issue number1
DOIs
StatePublished - Jan 2020
Externally publishedYes

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