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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...