HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Abstract

Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.

Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis

“…Despite the remarkable successes in animal experiments, most approved agents have proven insufficient to cure human patients. A lack of appropriate indicators is one of the important causes for this failure; therefore, developing biomarkers for MET-targeting therapy might represent an effective approach to improve its therapeutic efficiency in PDAC [45,46]. In the present study, we found that overexpression of circBFAR significantly increased the expression of MET in PDAC.…”

Machine Learning-Guided Prediction of Antigen-Reactive In Silico Clonotypes Based on Changes in Clonal Abundance through Bio-Panning

“…Small molecule inhibitors specific to c-Met are yet to be approved, and only nonspecific tyrosine kinase inhibitors inhibiting c-Met are available (Table 3) [27]. Recombinant protein (truncated HGF, decoy c-Met) was not successful in clinical trials due to several factors, including short half-life and low target affinity limiting the intended efficacy [28]. Several HGF-neutralizing antibodies have been developed with two currently active in clinical trials [29].…”

Impact of MET alterations on targeted therapy with EGFR-tyrosine kinase inhibitors for EGFR-mutant lung cancer

“…This induces the recruitment of several intracellular effector adaptor proteins, such as growth factor receptor binding protein 2 (Grb2), GAB1, SRC and PI3K, thereby activating downstream signaling pathways [14,16]. The HGF/MET signaling pathway is expressed in both embryonic and adult bodies under certain physiological conditions [17]. During embryonic development, the HGF/MET signaling pathway plays an important role in promoting mitosis and inducing morphogenesis; in adults, this signaling pathway plays a role in repair and regeneration after tissue damage.…”

“…Currently, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors are currently in trials for different settings [34,[36][37][38]. MET inhibitors can be divided into three categories: small molecule MET receptor inhibitors (such as crizotinib, tivantinib, savolitinib, tepotinib, cabozantinib and foretinib), monoclonal antibodies targeting the MET receptor (such as onartuzumab) and anti-HGF antibodies (such as ficlatuzumab and rilotumumab) [17,[39][40][41][42][43][44]. Some MET inhibitors in combination with EGFR-TKIs have been studied in patients, but this treatment regimen has not shown significant efficacy in patients with unselected NSCLC.…”