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 therapy1. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance2,3. The identification of resistance mechanisms has revealed a recurrent theme—the engagement of survival signals redundant to those transduced by the targeted kinase4. 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)5. Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma6 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.

Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM

“…Several studies have demonstrated that activation of receptor tyrosine kinases by their corresponding growth factors can render PLX4032-sensitive melanoma cells resistant to apoptosis. 16,17 In accordance with these studies, we found that HGF could rescue cMET+ BRAF mutant melanoma cell lines from PLX4032-induced killing, whereas those melanoma lines lacking cMET did not acquire resistance. Importantly, we were able to demonstrate that resistance to PLX4032 caused by HGF was associated with a reduction in PUMA and BIM protein levels rather than an increase in the levels of pro-survival BCL-2-like proteins.…”

“…15 Recent studies have implicated HGF/cMET signalling as an important resistance mechanism acquired by BRAF mutant melanoma cells following PLX4032 treatment. 16,17 HGF mediates its activity through activation of the cMET receptor tyrosine kinase that is expressed on the surface of human melanoma cell subsets. 30 We quantified cMET expression on the BRAF V600E melanoma cells by flow cytometry, classifying them as cMET+ or cMET-(Supplementary Figure 4a).…”

“…15 Specifically, it was reported that secretion of hepatocyte growth factor (HGF) from the tumour microenvironment and consequent activation of its receptor tyrosine kinase, cMET, which is expressed on a subset of the melanoma cells, promotes outgrowth of PLX4032-resistant cancer cells. 16,17 In this study, we examined the importance of the intrinsic apoptotic pathway in PLX4032-induced killing of melanoma cells and its role in HGF/cMET signalling-driven resistance to this drug. Understanding these mechanisms will be crucial for the identification of novel therapeutic targets in BRAF V600E melanomas and possibly other cancers that express cMET.…”

Pharmaceutical properties of supramolecular assembly of co-loaded cardanol/triazole-halloysite systems

“…Over 80% of liver cancer patients are diagnosed with hepatocellular carcinoma, which is resistant to most conventional chemotherapeutic agents (Wilson et al, 2012). Moreover, the use of chemoprevention agents is typically associated with side effects that lead to the destruction of normal tissues, such as those of the digestive, hematopoietic and nervous systems (Meyskens and Gerner, 1999;Suzuki et al, 2008;Florea and Büsselberg, 2011).…”

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…As recently shown, the sensitivity of cancer cells to TKIs can be impaired by the increased availability of growth factor ligands. More specifi cally, when testing different growth factors on a series of kinase-addicted cancer cell lines that are sensitive to specifi c TKIs, hepatocyte growth factor, FGFs, and neuregulin seem to confer drug resistance to most of the cells ( 58 ). Interestingly, the secretion of these ligands may come from tumor stroma ( 59 ).…”