Therapy-induced tumour secretomes promote resistance and tumour progression Journal Article

Authors: Obenauf, A. C.; Zou, Y. L.; Ji, A. L.; Vanharanta, S.; Shu, W. P.; Shi, H. B.; Kong, X. J.; Bosenberg, M. C.; Wiesner, T.; Rosen, N.; Lo, R. S.; Massague, J.
Article Title: Therapy-induced tumour secretomes promote resistance and tumour progression
Abstract: 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.
Keywords: melanoma; metastasis; microenvironment; drug-resistance; inhibitors; kinase; cns; acquired-resistance; translational profiling approach; raf inhibitor resistance; cell-types; cancer chemoresistance
Journal Title: Nature
Volume: 520
Issue: 7547
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2015-04-16
Start Page: 368
End Page: 372
Language: English
ACCESSION: WOS:000352974200043
DOI: 10.1038/nature14336
PUBMED: 25807485
PMCID: PMC4507807
Notes: Article -- Source: Wos
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MSK Authors
  1. Neal Rosen
    356 Rosen
  2. Joan Massague
    276 Massague
  3. Weiping Shu
    16 Shu
  4. Thomas Wiesner
    38 Wiesner
  5. Anna Obenauf
    11 Obenauf
  6. Andrew Lin Ji
    1 Ji
  7. Yilong Zou
    13 Zou