The role of mutational activation of RAS and PI3K signaling pathways in human tumors: Biologic and therapeutic implications

Mutational activation of KRAS is a common event in human tumors and is thought to play an important role in their ontogeny. Activated KRAS signals through multiple effectors including RAF-MEK-ERK, PI3K-AKT and RalGEFs. We have classified KRAS mutated tumors by their dependence on MEK/ERK activity. A subset of KRAS mutated tumors are sensitive to pharmacologic inhibition of MEK-ERK activity, which results in inhibition of anchorage-dependent and independent proliferation in vitro, induction of apoptosis and profound suppression of tumor growth in vivo. However, a large proportion of these tumors are insensitive to MEK inhibition. Tumor cells that do not require ERK signaling also do not rely on KRAS expression for proliferation. Coexistent PI3K mutations occur in a significant number of tumors with KRAS mutation. MEK/ERK-dependent tumors are PI3K wild-type and their growth in vivo is effectively suppressed by MEK inhibition, whereas tumors with both mutations are not dependent on KRAS for proliferation or on ERK signaling for transformation and growth in vivo. Knock-out of the mutant PI3K allele restores both KRAS and MEK/ERK dependence. The results suggest that some KRAS mutant cancers depend upon MEK/ERK to maintain transformation but that acquisition of a PI3K mutation relieves their dependence on both KRAS and ERK. In fact, we find that tumor xenografts with coexisting KRAS and PI3K mutations do not respond to MEK inhibition alone, but are however sensitive to combined inhibition of both MEK-ERK and PI3K-AKT pathways.;RAS mutation is a common event in human malignancy, yet attempts to develop therapies that directly target RAS have been unsuccessful. Another feasible therapeutic strategy involves inhibition of RAS effector pathways. The results here define genotypes that suggest which KRAS tumors may be effectively treated with MEK inhibition and support the possibility that MEK/ERK inhibition, alone or in combination with inhibition of PI3K/AKT signaling may be effective therapeutic strategies for mutant KRAS-dependent malignancy.