Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors.
Nature
; 487(7408): 505-9, 2012 Jul 26.
Article
in En
| MEDLINE
| ID: mdl-22763448
ABSTRACT
Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance. The identification of resistance mechanisms has revealed a recurrent themethe engagement of survival signals redundant to those transduced by the targeted kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell-survival effectorsmost notably, phosphatidylinositol-3-OH kinase (PI(3)K) and mitogen-activated protein kinase (MAPK). Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signalling output. Here, using a panel of kinase-'addicted' human cancer cell lines, we found that most cells can be rescued from drug sensitivity by simply exposing them to one or more RTK ligands. Among the findings with clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.
Full text:
1
Database:
MEDLINE
Main subject:
Sulfonamides
/
Breast Neoplasms
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Hepatocyte Growth Factor
/
Drug Resistance, Neoplasm
/
Proto-Oncogene Proteins B-raf
/
Protein Kinase Inhibitors
/
Indoles
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Melanoma
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Nature
Year:
2012
Type:
Article
Affiliation country:
United States