Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies

Musalula Sinkala,Nicola Mulder,Darren Patrick Martin,Panji Nkhoma

doi:10.1038/s42003-020-01552-6

Abstract

The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells. The molecular aberrations which lead to cancer involve mutations in, and transcription variations of, various MAPK pathway genes. Here, we examine the genome sequences of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We show that patients with tumours that have mutations within genes of the ERK-1/2 pathway, the p38 pathways, or multiple MAPK pathway modules, tend to have worse disease outcomes than patients with tumours that have no mutations within the MAPK pathways genes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the re sponses of cancer cells to MAPK targeting drugs: a revelation with great potential for guiding the development of innovative therapies.

Highlights

The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells
Besides providing novel biological insights into the mutational landscape of MAPK pathway genes, and how these affect disease outcomes in cancer patients, we show both the specific MAPK pathway genes that impact the fitness of cancer cells and how vulnerabilities exposed by mutations and transcriptional changes in these genes are reflected in the responses of cancer cells to MAPK pathway inhibitors
We found that patients with tumours that had mutations in Jun Nterminal kinase (JNK) pathway genes had the most favourable overall survival (OS) and disease-free survival (DFS) outcomes, a finding that is consistent with other studies that have shown an association between alterations in JNK pathway genes and both enhanced apoptosis[37,38,39] and improved survival outcomes[37,38,40] (Fig. 2f, g)

Summary

Introduction

The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells. The mitogen-activated protein kinase (MAPK) pathways are crucial cell signal transduction pathways that regulate molecular processes such as cell proliferation, cell differentiation, cell survival, cancer dissemination, and resistance to drug therapy[1,2]. The MAPK pathways involve four main modules: the extracellular-signal-regulated kinase 1 and 2 (ERK1/2) pathway ( known as the classical pathway), the c-Jun Nterminal kinase (JNK) pathway, the p38 pathway and the ERK5 pathway[1,3] Each of these modules is initiated by specific extracellular signals that lead to the sequential activation of a MAP kinase kinase kinase (MAPKKK), a MAP kinase kinase (MAPKK) which phosphorylates a MAP kinase (MAPK)[1,2,3]. Several genetic aberrations, including mutations in, and copy number variations of, MAPK pathway genes have been identified in human cancers, and several of the proteins encoded by these genes are promising drug targets[14,15,16,17]. A better appreciation of the specific MAPK pathway aberrations in different human cancers would likely translate to improved disease outcome predictions because some of the genetic alterations of cancer cells are likely to be directly associated with disease aggressiveness and clinical outcomes

Methods

Results

Conclusion