Journal Article

Cancer drug addiction is relayed by an ERK2-dependent phenotype switch

Kong, Xiangjun, Peeper, Daniel S., Kuilman, Thomas, Rozeman, Elisa A., Kemper, Kristel, Song, Ji-Ying, Boshuizen, Julia, Geukes Foppen, Marnix H., Niessen, Hans W. M., Shahrabi, Aida, Blank, Christian U.

2017

Overview

The identification of an ERK2–JUNB–FRA1 signalling pathway that drives addiction to therapeutic drugs in cancer cells, and an ERK2-dependent phenotype switch that precedes cell death after drug withdrawal, may help to guide therapies that exploit the addiction phenotype. Exploiting cancer's drug habit Cancer cells can acquire drug resistance through different genetic and non-genetic mechanisms. In some cases, drug-resistant cells become addicted to the treatment and can die upon drug withdrawal. The authors explore the mechanistic basis for this drug addiction in melanoma cells, and identify a phenotype-switch pathway that is triggered by targeted therapy. The findings suggest that alternating therapies could be tailored to exploit the drug-addiction phenotype of therapy-resistant cancer cells. Observations from cultured cells 1 , 2 , 3 , animal models 4 and patients 5 , 6 , 7 raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR–Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for ‘addiction genes’. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial–mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/95 / 49/39 / 49/47 / 49/91 / 631/67/1059/602 / 631/67/1813/1634 / 64/60 / 82/51 / Animals / Antineoplastic agents / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - pharmacology / Apoptosis / Axl protein / B-cell lymphoma / Bcl-2 protein / Cancer / Cancer therapies / Cell Death - drug effects / Cell Line, Tumor / Complications and side effects / CRISPR / CRISPR-Cas Systems - genetics / Dacarbazine / Deoxyribonucleic acid / DNA / DNA damage / Drug abuse / Drug addiction / Drug dosages / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - physiology / Epithelial-Mesenchymal Transition / Extracellular signal-regulated kinase / Female / Fra1 protein / Gene Editing / Genes / Genetic aspects / Genomes / Genotype & phenotype / Health aspects / Humanities and Social Sciences / Humans / JunB protein / Kinases / Lethality / letter / Lung cancer / Lung diseases / Lung Neoplasms - drug therapy / Lung Neoplasms - enzymology / Lung Neoplasms - pathology / Lymphocytes B / Lymphoma / MAP Kinase Signaling System - drug effects / Melanoma / Melanoma - drug therapy / Melanoma - enzymology / Melanoma - pathology / Mesenchyme / Mice / Mice, Knockout / Microphthalmia-associated transcription factor / Microphthalmia-Associated Transcription Factor - metabolism / Mitogen-Activated Protein Kinase 1 - metabolism / Molecular Targeted Therapy / multidisciplinary / Mutation / Patients / Phenotype / Phenotypes / Phosphotransferases / Protein-tyrosine kinase receptors / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Science / Signal transduction / Signaling / Skin cancer / Transcription factors / Transcription Factors - metabolism / Tumors / Tyrosine / Vulnerability / Withdrawal