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Nature. 2015 Apr 16;520(7547):368-72. doi: 10.1038/nature14336. Epub 2015 Mar 25.

Therapy-induced tumour secretomes promote resistance and tumour progression.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
2
1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Gerstner Sloan Kettering School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
3
1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
4
Division of Dermatology, Department of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA.
5
1] Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
7
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Abstract

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.

PMID:
25807485
PMCID:
PMC4507807
DOI:
10.1038/nature14336
[Indexed for MEDLINE]
Free PMC Article

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