title: Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors.
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 theme—the 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 effectors—most 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.
authors: Research Oncology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Timothy R
authors: TR
authors: Wilson
authors: Jane
authors: J
authors: Fridlyand
authors: Yibing
authors: Y
authors: Yan
authors: Elicia
authors: E
authors: Penuel
authors: Luciana
authors: L
authors: Burton
authors: Emily
authors: E
authors: Chan
authors: Jing
authors: J
authors: Peng
authors: Eva
authors: E
authors: Lin
authors: Yulei
authors: Y
authors: Wang
authors: Jeff
authors: J
authors: Sosman
authors: Antoni
authors: A
authors: Ribas
authors: Jiang
authors: J
authors: Li
authors: John
authors: J
authors: Moffat
authors: Daniel P
authors: DP
authors: Sutherlin
authors: Hartmut
authors: H
authors: Koeppen
authors: Mark
authors: M
authors: Merchant
authors: Richard
authors: R
authors: Neve
authors: Jeff
authors: J
authors: Settleman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000077341:Lapatinib; D008024:Ligands; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D017228:Hepatocyte Growth Factor; D007211:Indoles; D000077341:Lapatinib; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human