Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2.

Genetic disruption of the RAS binding domain (RBD) of Phosphoinositide 3-kinase alpha(PI3Kα) impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not impact PI3Kα's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3Kα interaction may represent a strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3Kα lipid kinase activity. We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block RAS activation of PI3Kα activity. In mice, inhibitors slow the growth of RAS mutant tumors and Human Epidermal Growth Factor Receptor 2 (HER2) overexpressing tumors, particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway, without causing hyperglycemia. Oncogenic mutations in the small guanosine triphosphatase RAS occur in 20% of human cancers, with RAS proteins activating both the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways (1-3). As each of these pathways has oncogenic potential, simultaneous activation, as occurs in mutant RAS driven cancers, generates aggressive disease. In RAS-driven cell and animal models, inhibition of both the MAPK and PI3K pathways is more efficacious than targeting the individual pathways (4); however, dose-limiting toxicities in humans prevent clinical success of this strategy. Although physiological activation of the MAPK pathway is RAS-dependent, the interaction between RAS and the catalytic subunit of PI3Kα, p110α, serves as an amplifier but not a primary activator of this pathway, and is less important in normal cellular regulation than it is in cancer (5).