American Association for Cancer Research
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Supplementary Table S1 from Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer

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journal contribution
posted on 2023-04-03, 22:25 authored by 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. Campbell, Emanuel F. Petricoin, Dhirendra K. Simanshu, Andrew J. Aguirre, Brian M. Wolpin, Krister Wennerberg, Udo Rudloff, Adrienne D. Cox, Channing J. Der

Structure factors and crystal information



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Lustgarten Pancreatic Cancer Foundation


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Dana-Farber Cancer Institute

Doris Duke Charitable Foundation

Pancreatic Cancer Action Network


American Cancer Society


Deutsche Forschungsgemeinschaft

Northeastern Collaborative Access Team beamline

Advanced Photon Source



United States Department of the Air Force

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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-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, 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. 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 deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.See related commentary by Falcomatà et al., p. 23.This article is highlighted in the In This Issue feature, p. 1