Editors' ChoiceCancer

Less is more for anticancer therapy combinations

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Science Translational Medicine  11 Oct 2017:
Vol. 9, Issue 411, eaap8166
DOI: 10.1126/scitranslmed.aap8166

Abstract

Withdrawal of MAPK inhibition sensitizes cancer cells to DNA repair–targeting drugs.

Targeted inhibition of proteins in the mitogen-activated protein kinase pathway (MAPK), including inhibition of kinases BRAF and MEK, often shows remarkable short-term efficacy in treating malignant melanoma with activating V600 mutations in BRAF. Unfortunately, resistance to MAPK inhibitors (MAPKi) almost inevitably emerges, and disease typically progresses within 12 months. A growing body of research has identified various mechanisms of resistance, including rewired signaling in alternative pathways, along with additional mutations in the MAPK pathway itself. Intriguingly, recent work has shown that inhibitor-induced reconfiguration of cell signaling pathways can result in so-called drug “addiction,” whereby cancer cells actually become dependent on MAPKi exposure for their proliferation and survival. However, the mechanisms of how MAPKi addiction occurs and how it may be co-opted with other therapeutic strategies, remain unclear.

Hong and colleagues addressed these issues using a panel of MAPKi-resistant melanoma cell lines, patient-derived xenografts, and an immunocompetent mouse model. Consistent with MAPKi addiction, the withdrawal of MAPKi across a panel of MAPKi-resistant cell lines caused slowed proliferation and increased cell death. Of note, withdrawal did not induce cell death through caspase-mediated apoptosis. Instead, it caused parthanatos-related programmed cell death associated with poly(ADP-ribose) accumulation and nuclear translocation of apoptosis-inducing factor. The extent of rebound in phosphorylated ERK (p-ERK), which indicates reactivation of the MAPK pathway, correlated with slowed proliferation and increased parthanatos. Using U.S. Food and Drug Administration–approved drugs, the authors exploited the drug addiction by combining MAPKi withdrawal with either (i) the DNA repair-targeted poly(ADP-ribose) polymerase inhibitor olaparib, to enhance DNA damage and parthanatos, and/or (ii) the BRAF inhibitor vemurafenib, to paradoxically enhance p-ERK and subsequent cell death in tumors with NRAS mutation or BRAF mutation outside the typical V600 site, which have historically been difficult to treat with MAPKi.

No drug combinations were curative, and it will be important to consider how MAPKi addiction may influence immune checkpoint blockade therapies. Nevertheless, the authors used a variety of methods and controls to demonstrate how removing MAPKi treatment can create new susceptibilities, thus improving response to subsequently administered drugs.

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