Therapy-induced tumour secretomes promote resistance and tumour progression

Article

关键词: TRANSLATIONAL PROFILING APPROACH;    ACQUIRED-RESISTANCE;    DRUG-RESISTANCE;    RAF INHIBITORS;    MELANOMA;    SURVIVAL;    EVOLUTION;   

DOI  :  10.1038/nature14336

来源: SCIE

【 摘 要 】

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer(1,2). 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 down-regulation 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.

【 授权许可】

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