Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer.

Allele-specific signaling by different KRAS alleles remains poorly understood. The KRAS(G12R) mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (similar to 1%) in lung and colorectal cancers, yet relatively common (similar to 20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRAS(G12R) is functionally distinct from the more common KRAS(G12D)- or KRAS(G12V)-mutant proteins (KRASG(12D/V)). We found that KRAS(G12D/V) but not KRAS(G12R) drives macropinocytosis and that MYC is essential for macropinocytosis in KRAS(G12D/V)- but not KRAS(G12R)-mutant PDAC. Surprisingly, we found that KRAS(G12R) is defective for interaction with a key effector, p110 alpha PI3K (PI3K alpha), due to structural perturbations in switch II. Instead, upregulated KRAS-independent P13K gamma activity was able to support macropinocytosis in KRAS(G12R)-mutant PDAC. Finally, we determined that KRAS(G12R)-mutant PDAC displayed a distinct drug sensitivity profile compared with KRAS(G12 D)-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRAS(G12R) is impaired in activating a key effector, p110 alpha PI3K. As such, KRAS(G1)(2R) is impaired in driving macropinocytosis. However, overexpression of PI3K gamma 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.