Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
| Autor: | Udo Rudloff, J. Nathaniel Diehl, G. Aaron Hobbs, Emanuel F. Petricoin, Channing J. Der, Adrienne D. Cox, Raymond W.S. Ng, Kirsten L. Bryant, Mariaelena Pierobon, Nicole M. Baker, Andrew J. Aguirre, Richard G. Hodge, Timothy H. Tran, Junning Wang, Andrew O. Anderson, Dominic Esposito, Anne M. Miermont, Adele Waters, Craig M. Goodwin, Bjoern Papke, Krister Wennerberg, Jonathan M. DeLiberty, Sharon L. Campbell, Jennifer E. Klomp, Prson Gautam, Dhirendra K. Simanshu, Ryan D. Thurman, Brian M. Wolpin |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mutation endocrine system diseases Effector Autophagy P110α Biology medicine.disease_cause medicine.disease digestive system diseases 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis Pancreatic cancer Cancer research medicine KRAS Carcinogenesis PI3K/AKT/mTOR pathway |
| Zdroj: | Cancer Discovery. 10:104-123 |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-19-1006 |
| Popis: | 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.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 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 |
| Databáze: | OpenAIRE |
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