The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Therapy-induced tumour secretomes promote resistance and tumour progression
Open accessAbstract
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.
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Metastatic colonization by circulating tumour cells
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Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance
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Self-citationSurviving at a Distance: Organ-Specific Metastasis
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Metadata
- Authors
- Obenauf, A. C., Zou, Y., Ji, A. L., Vanharanta, S., Shu, W., Shi, H., Kong, X., Bosenberg, M. C., Wiesner, T., Rosen, N., Lo, R. S., & Massagué, J.
- Venue
- Nature
- Published
- 2015-03-25
- Volume
- 520
- Issue
- 7547
- Pages
- 368-372
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2092437923
- Cited by
- 494
- References
- 38
- FWCI
- 25.86
- Type
- journal article
- Language
- en
- Open access
- green
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