Abstract PR6: Widespread potential for growth factor-driven resistance to anti-cancer kinase inhibitors

• Published in: Clinical cancer research Vol. 18; no. 10_Supplement; p. PR6
• Main Authors: Wilson, Timothy R., Fridlyand, Jane, Ribas, Antoni, Li, Jiang, Koeppen, Hartmut, Merchant, Mark, Neve, Richard, Settleman, Jeff, Yan, Yibing, Penuel, Elicia, Burton, Luciana, Chan, Emily, Peng, Jing, Lin, Eva, Wang, Yulei, Sosman, Jeff
• Format: Journal Article
• Language: English
• Published: 15.05.2012
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.MECHRES-PR6

Abstract Mutationally activated kinases, including EGFR, HER2, ALK, ABL, PDGFR, c-KIT, and BRAF, define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumors harbor such alleles is invariably limited by innate or acquired drug resistance. As molecular mechanisms of resistance have begun to be elucidated, a recurrent theme is the engagement of survival signals redundant to those transduced by the targeted oncogenic kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs), and many of these can potentially mediate signals that converge on common and critical downstream cell survival effectors - most notably, PI-3 kinase (PI3K) and MAP kinase (MAPK). Consequently, an increase in RTK ligand levels, via autocrine tumor cell production, paracrine contribution by tumor stroma, or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar downstream signaling output. Indeed, using a large panel of kinase-“addicted” cancer cell lines, we found that the vast majority of such cells can be “rescued” from drug sensitivity by simply exposing them to one or more RTK ligands that engage redundant survival effectors. Among the findings with immediate clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the HER2 kinase inhibitor lapatinib in HER2 amplified breast cancer cells, and to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF mutant melanoma cells. Analysis of systemic HGF levels from PLX4032-treated BRAF mutant metastatic melanoma patients who were enrolled on the BRIM2 study indicated that increased HGF levels were significantly associated with a worse clinical outcome. These observations highlight the extensive redundancy of RTK-transduced signaling in cancer cells and the potentially broad role of widely expressed RTK ligands in both innate and acquired resistance to drugs targeting oncogenic kinases. This proffered talk is also presented as Poster B38.