Developing biomarkers to predict benefit from HGF/MET pathway inhibitors

Abstract

Activation of the MET signalling pathway is critical in regulating multiple cellular processes underlying tumourigenic growth and has represented an attractive target for therapeutic intervention in cancer. Early stage clinical studies of multiple agents targeting this pathway have been undertaken, frequently in unselected patient cohorts with variable results. Promising data in patient subgroups in these studies indicate the need for predictive biomarkers to identify the patients most likely to benefit from these therapies. In this review, we discuss the current knowledge of mechanisms of MET activation, the status of the clinical evaluation of MET-targeted therapies, the associated efforts to identify and validate biomarkers, and the considerations and challenges for potential development of companion diagnostics.

Analysis and significance of c-MET expression in adenoid cystic carcinoma of the salivary gland

“…The prognostic value of c-MET overexpression seems to be tumor dependent and somehow controversial., While copy number gain and amplification has been shown to enhance tumor growth, invasiveness and promote metastasis in certain tumor types as esophageal, lung adenocarcinoma, and colon cancer, [6][7][8]9 in other tumor types such as breast, lung squamous cell carcinoma, and tonsil squamous cell carcinoma, its overexpression has either no prognostic relevance or is associated with improved patient's outcomes. [10][11][12][13] To ascertain whether aberrant c-Met expression accompanies human salivary ACC, we used immunohistochemical analysis to examine c-Met protein expression in 200 samples and concluded that 52% of tumors are strongly positive.…”

“…While a predictive biomarker for c-MET inhibitors benefit has not been fully established, c-MET protein expression is the strongest candidate and is being used to select patients for participation in clinical trials with c-MET inhibitors single agent or in combination. 7 Given the high percentage of salivary gland ACC with strong c-MET expression, and the absence of standard of care systemic therapy for this orphan disease, evaluation of c-MET overexpression as a predictive marker of benefit of c-MET inhibitors deserves further investigation in clinical trials.…”

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…Furthermore, elevated HGF levels are observed in a number of disease settings, including virus/bacterial infections, graft-versus-host disease, and following surgical procedures, making their use as a biomarker for selection of patients less favourable [89][90][91]. It is also yet to be vigorously validated how circulating HGF levels relate to HGF levels within the tumour micro-environment [92]. Because HGF is a secreted, soluble, factor, it must be noted that HGF within the tumour tissue may not have been generated locally.…”

MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy

“…In recent retrospective studies in which the expression of MET was determined by this approach in gastric tumor specimens obtained after tumor resection, MET overexpression was detected in 4-63 % of cases [64][65][66][67][68][69]. Possible reasons for this wide variation in the frequency of this biomarker include the absence of consensus on scoring criteria for MET immunohistochemistry, encompassing the use of different sample types, interreader variability, and differences in tissue processing and storage, primary and secondary antibodies, staining protocols, and scoring methods [70,71]. Furthermore, increased MET expression in the absence of gene amplification can occur in a manner independent of HGF [72,73] and as a result of transcriptional upregulation by the products of other oncogenes [74,75], environmental conditions such as hypoxia [76], and agents secreted by reactive stroma such as inflammatory cytokines and proangiogenic factors [77].…”