期刊
NATURE
卷 520, 期 7547, 页码 368-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature14336
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资金
- AACR [SU2C]
- MSK Metastasis Research Center
- NIH [CA163167, CA129243]
- Congressionally Directed Medical Research Program of the Department of Defense
- Howard Hughes Medical Institute
- Cancer Center [P30 CA008748]
- Erwin Schroedinger Fellowship (FWF, Austrian Science Fund) [J3013]
- Medical Research Council
- Austrian Science Fund (FWF) [J3013] Funding Source: Austrian Science Fund (FWF)
- Medical Research Council [MC_UU_12022/7, MC_UP_1101/4] Funding Source: researchfish
- MRC [MC_UU_12022/7] Funding Source: UKRI
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.
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