Publication Date:
2015-03-26
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507807/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507807/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Obenauf, Anna C -- Zou, Yilong -- Ji, Andrew L -- Vanharanta, Sakari -- Shu, Weiping -- Shi, Hubing -- Kong, Xiangju -- Bosenberg, Marcus C -- Wiesner, Thomas -- Rosen, Neal -- Lo, Roger S -- Massague, Joan -- CA129243/CA/NCI NIH HHS/ -- CA163167/CA/NCI NIH HHS/ -- J 3013/Austrian Science Fund FWF/Austria -- MC_UU_12022/7/Medical Research Council/United Kingdom -- P01 CA094060/CA/NCI NIH HHS/ -- P01 CA129243/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA176111/CA/NCI NIH HHS/ -- U54 CA163167/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Apr 16;520(7547):368-72. doi: 10.1038/nature14336. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 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. ; 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. ; Division of Dermatology, Department of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA. ; 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. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807485" target="_blank"〉PubMed〈/a〉
Keywords:
Adenocarcinoma/drug therapy/metabolism/pathology/secretion
;
Animals
;
Cell Line, Tumor
;
Cell Movement/drug effects
;
Cell Proliferation/drug effects
;
Cell Survival/drug effects
;
Clone Cells/drug effects/pathology
;
*Disease Progression
;
Down-Regulation/drug effects
;
Drug Resistance, Neoplasm/*drug effects
;
Enzyme Activation/drug effects
;
Female
;
Humans
;
Lung Neoplasms/drug therapy/metabolism/pathology/*secretion
;
Melanoma/drug therapy/metabolism/pathology/*secretion
;
Metabolome/*drug effects
;
Mice
;
Neoplasm Metastasis/drug therapy/pathology
;
Protein Kinase Inhibitors/*pharmacology/*therapeutic use
;
Proto-Oncogene Proteins B-raf/antagonists & inhibitors
;
Proto-Oncogene Proteins c-akt/metabolism
;
Proto-Oncogene Proteins c-fos/deficiency
;
Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
;
Receptor, Epidermal Growth Factor/antagonists & inhibitors
;
Signal Transduction/drug effects
;
Tumor Microenvironment/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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