Abstract

The RAS pathway is one of the most frequently deregulated pathways in cancer. RAS signals through multiple effector pathways, including the RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascades. The oncogenic potential of these effector pathways is illustrated by the frequent occurrence of activating mutations in BRAF and PIK3CA as well as loss-of-function mutations in the tumor suppressor PTEN, a negative regulator of PI3K. Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response. The molecular mechanisms responsible for this heterogeneous response remain unclear. In this study, we show that PI3K pathway activation strongly influences the sensitivity of RAS mutant cells to MEK inhibitors. Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance. We further show that down-regulation of PIK3CA resensitizes cells with co-occurring KRAS and PIK3CA mutations to MEK inhibition. At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death. Finally, we show that whereas inactivation of either the MEK or PI3K pathway leads to partial tumor growth inhibition, targeted inhibition of both pathways is required to achieve tumor stasis. Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.

Highlights

  • RAS is one of the most frequently mutated oncogenes in human cancer [1]

  • To identify molecular modifiers that influence the sensitivity of KRAS mutant cancers to MEK pathway inhibition, we profiled a panel of cancer cell lines to determine their response to the MEK1/2 inhibitor PD0325901, which inhibits extracellular signal-regulated kinase (ERK) phosphorylation with an IC50 of 10 to 20 nmol/L

  • Four of five cell lines that harbor KRAS mutations but have a wild-type phosphatidylinositol 3-kinase (PI3K) pathway are very sensitive to MEK inhibitor treatment (Fig. 1A, light gray columns), with IC50 values similar to those required for complete phospho-ERK suppression (Fig. 1B)

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Summary

Introduction

RAS is one of the most frequently mutated oncogenes in human cancer [1]. Oncogenic mutations in RAS lead to deregulation of several effector pathways that control cell proliferation, survival, and migration and promote malignant transformation. The best-characterized RAS effector pathway is the RAF-mitogen-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Lengauer: Sanofi-Aventis, 13 Quai Jules Guesde, 94403 Vitry-sur-Seine, France

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