MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models

Zheng Xue,Carlos Caldas,Oscar M Rueda,Tonci Sustic,Alejandra Bruna,Ankita Sati Batra,Evert Bosdriesz,Sake Van Wageningen,Lodewyk F A Wessels,René Bernards,Daniel J Vis

doi:10.1038/s41422-018-0044-4

Abstract

Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.

Highlights

The genetic aberrations that lie at the heart of cancer can create a dependency, a situation referred to as “oncogene addiction.”[1]
Recurrent MAP3K1 and MAP2K4 mutations sensitize cancer cells to MEK inhibitors To study whether the MAP3K1 and MAP2K4 mutations identified in breast cancers give rise to a vulnerability that can be exploited therapeutically, we used a panel of breast cancer cells lines that we sequenced previously.[12]
Among the 11 breast cancer cell lines, we found that MDA-MB-134VI and MPE600 had inactivating mutations in MAP2K4 (Supplementary information, Table S1)

Summary

Introduction

The genetic aberrations that lie at the heart of cancer can create a dependency, a situation referred to as “oncogene addiction.”[1]. RAS proteins connect growth factor signaling to multiple downstream pathways, including the RAF-MEK-ERK pathway ( known as the mitogen activated protein kinase (MAPK) pathway) and the PI3K pathway. These pathways contribute to oncogenesis through stimulation of cell proliferation and escape from apoptosis. Inhibition of RAF-MEK-ERK kinases can result in decrease in tumor cell proliferation and induce apoptosis.[5,6] Many pharmaceutical companies have developed MEK kinase inhibitors, but the clinical benefit of these inhibitors has been disappointing to date.[7,8,9] A notable exception is the use of MEK inhibitors in BRAF or NRAS mutant melanomas.[10,11] identifying predictive biomarkers for MEK inhibitor response and potential combination therapies that enhance MEK inhibitor effectiveness is essential for the future clinical use of these drugs. Recent large-scale genomic studies have identified oncogenic driver mutations in multiple cancers, including recurrent mutations in MAP3K1 and MAP2K4.12–14 The MAP3K1 and MAP2K4 mutations are loss-of-function mutations, including nonsense and frame shift mutations and a missense mutation (Ser56Leu), which interferes with MAP2K4 kinase activity.[12,13,15] The highest mutation frequency in these genes is found in invasive ductal breast cancers: MAP3K1 9% and MAP2K4 7%,16 followed by cancers of prostate, stomach and diffuse large B cell lymphoma[16,17,18,19,20,21]

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Results

Conclusion