Atypical KRAS G12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer

• Published in: Cancer discovery Vol. 10; no. 1; p. 104
• Main Authors: Hobbs, G Aaron, Baker, Nicole M, Miermont, Anne M, Thurman, Ryan D, Pierobon, Mariaelena, Tran, Timothy H, Anderson, Andrew O, Waters, Andrew M, Diehl, J Nathaniel, Papke, Bjoern, Hodge, Richard G, Klomp, Jennifer E, Goodwin, Craig M, DeLiberty, Jonathan M, Wang, Junning, Ng, Raymond W S, Gautam, Prson, Bryant, Kirsten L, Esposito, Dominic, Campbell, Sharon L, Petricoin, 3rd, Emanuel F, Simanshu, Dhirendra K, Aguirre, Andrew J, Wolpin, Brian M, Wennerberg, Krister, Rudloff, Udo, Cox, Adrienne D, Der, Channing J
• Format: Journal Article
• Language: English
• Published: United States 01-01-2020
• Subjects: Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pinocytosis; Proto-Oncogene Proteins p21(ras) - genetics; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 2159-8290

Allele-specific signaling by different KRAS alleles remains poorly understood. The
mutation displays uneven prevalence among cancers that harbor the highest occurrence of
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 KRAS
is functionally distinct from the more common KRAS
- or KRAS
-mutant proteins (KRAS
). We found that KRAS
but not KRAS
drives macropinocytosis and that MYC is essential for macropinocytosis in KRAS
- but not KRAS
-mutant PDAC. Surprisingly, we found that KRAS
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 KRAS
-mutant PDAC. Finally, we determined that KRAS
-mutant PDAC displayed a distinct drug sensitivity profile compared with KRAS
-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRAS
is impaired in activating a key effector, p110α PI3K. As such, KRAS
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.
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