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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Several MET pathway inhibitors like HGF inhibitors (ficlatuzumab), anti-MET monoclonal antibodies (onartuzumab), and MET tyrosine kinase inhibitors (crizotinib, tivantinib) are currently being studied in combination with EGFR-TKIs [50, 56] (Table 3). A study by Mok et al. involving 188 Asian patients with stage IIIB/IV lung adenocarcinoma, who received either ficlatuzumab and gefitinib or gefitinib alone, did not find any statistically significant improvement with the combination [56]. However, preliminary results in a subset of patients with both EGFR sensitizing mutations and low c-Met biomarker levels showed that the combination had a trend towards ORR and PFS improvement, and for prolonged OS in those with high stromal HGF (P = 0.03) [56]. In another phase II study, onartuzumab, a monovalent antibody against c-MET-, was associated with improved PFS and OS in the MET-positive population while the MET-negative patients had worse outcomes [57]. Sequist et al. compared erlotinib alone with the combination of erlotinib and tivantinib (ARQ 197), a non-patients in the study had MET gene copy number ≥ 4, equally distributed between the treatment arms. There were no statistically significant differences in PFS or OS, though the combination of erlotinib and tivantinib had a trend towards benefit in patients with increased MET gene copy number [58] (Table 3).
Hepatocellular carcinoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Daniel H. Palmer, Philip J. Johnson
A better understanding of the mechanisms of resistance to VEGF-targeted therapies may help improve therapeutic strategies. For example, there is evidence that hepatocyte growth factor signalling through its receptor, c-met, may play a role in mediating such resistance and, indeed, may contribute to the emergence of a more aggressive phenotype during anti-VEGF therapy. This suggests a potential role for c-met inhibition as a second-line strategy, or in combination with anti-angiogenic therapy. The c-met inhibitor ARQ197 has been investigated in a randomized phase II trial for patients with HCC and it significantly prolonged time to progression, the primary endpoint of the study, compared with best supportive care (hazard ratio, 0.64). An exploratory analysis of survival according to c-met expression assessed by immunohistochemistry on tumour biopsies suggested that c-met was an adverse prognostic factor and that patients with high c-met may derive greatest benefit from ARQ197, although this requires further prospective evaluation.67–71
Prediction of cytotoxic activity of a series of 1H-pyrrolo[2,3-b]pyridine derivatives as possible inhibitors of c-Met using molecular fingerprints
Published in Journal of Receptors and Signal Transduction, 2019
Tahereh Damghani, Korosh Mashayekh, Somayeh Pirhadi, Omidreza Firuzi, Shahrzad Sharifi, Najmeh Edraki, Mehdi Khoshneviszadeh, Mohammad Sadegh Avestan
To impede the c-Met signaling pathway, several approaches are exploited including blocking the interaction between c-Met and HGF via antibodies or antagonists and interfering with the active site of the kinase domain with small molecule kinase inhibitors. A number of small molecule inhibitors that bind to the ATP binding pocket of c-Met protein have been developed to inhibit the activity of c-Met kinase (Figure 1) [8–14]. Some of them have currently progressed into clinical trials or have been approved by the U.S. Food and Drug Administration [14]. Through the analysis of binding modes, the c-Met kinase inhibitors could be roughly classified into three types. Type I c-Met inhibitors bind to ATP binding site with a U-shaped binding mode, which often interacts with the residues in the hinge region (Pro1158, Tyr1159, and Met1160). In general, type I inhibitors (such as crizotinib) exhibit good selectivity for c-Met and are expected to cause fewer side effects in cancer treatment [8]. Type II c-Met kinase inhibitors such as cabozantinib are often multi-kinase inhibitors and adopt extended conformations that pass the gatekeeper and occupy the deep hydrophobic back pocket. Aside from the above-mentioned well-classified inhibitors, there are other atypical c-Met inhibitors, such as ARQ197, which could be classified as type III c-Met inhibitors [13].
Optimization techniques for novel c-Met kinase inhibitors
Published in Expert Opinion on Drug Discovery, 2019
Zhi-Gang Sun, Yong-An Yang, Zhi-Gang Zhang, Hai-Liang Zhu
Crizotinib was the first c-Met inhibitor approved by the US Food and Drug Administration (FDA) in 2011 [18]. Crizotinib received another approval to treat patients with non-small cell lung cancer (NSCLC) by the US FDA [19]. Cabozantinib was approved for the treatment of medullary thyroid cancer in November 2012 [20] and is in clinical trials for the treatment of prostate [21], bladder, ovarian, breast [22], melanoma [23], NSCLC [24], hepatocellular [25], and kidney cancers [26]. Several small molecule inhibitors are under clinical evaluation. Tivantinib (ARQ197) was reported that a phase III clinical trial for advanced hepatocellular carcinoma failed to meet the initial goal, and many other clinical trials of tivatinib have been studied [27–32]. Foretinib, likewise, has been under many clinical studies for treating different cancers as single-agent or combinational agent [33–37]. The potential value of c-Met inhibitors in the treatment of cancer highlights the importance of developing new c-Met inhibitors, especially with the rise of drug resistance.
Renal Cell Carcinoma: genomic landscape and clinical implications
Published in Expert Review of Precision Medicine and Drug Development, 2020
Gaetano Aurilio, Matteo Santoni, Alessia Cimadamore, Francesco Massari, Marina Scarpelli, Antonio Lopez-Beltran, Liang Cheng, Nicola Battelli, Franco Nolé, Rodolfo Montironi
c-MET is the tyrosine kinase receptor for hepatocyte growth factor, involved in cancer cell proliferation, angiogenesis VEGF driven, and tumor metastasization. The prognostic significance of c-Met in patients with RCC has been largely investigated over the years, however its real implications are yet a matter of debate. Gibney et al. have investigated the expression of c-Met and its inhibition under SU11274 and ARQ 197 in a large cohort of RCC tumors and cell lines. The authors observed that the expression of c-Met was prominent in papillary type 1 and sarcomatoid tumors, as well as in low grade differentiation- and advanced stage tumors. As regards survival outcomes, higher c-Met expression was significantly associated with worse specific-disease survival and resulted an independent predictive factor of survival [27]. Schutz and colleagues retrospectively assessed the correlation between genotype via germline DNA samples and recurrence-free survival in 554 RCC patients after nephrectomy. The findings showed that patients harboring a novel c-Met single nucleotide polymorphisms (rs11762213) had a significant risk of recurrence or death at multivariate analysis. Median recurrence-free survival resulted equal to 19 months for patients carriers the risk allele versus 50 months months for patients without the risk allele [28]. A few years later, Hakimi et al. further investigated the prognostic role of c-Met variant rs11762213 in a large population of ccRCC patients. The results showed that the risk allele was confirmed to be significantly correlated with adverse CSS and time to recurrence. The authors, therefore, suggested this c-Met polymorphism as a new prognostic tool to be included in daily clinical practice [29]. More recently, a meta-analysis addressing the prognostic value of c-Met expression has been conducted in 1724 RCC patients. The results showed that high versus low c-Met tumor expression correlated with significantly worse OS, suggesting a role of c-Met as prognosticator for patients with RCC. The authors however underlined some drawbacks, such as (i) the small number of studies included in the meta-analysis (n = 12); (ii) the retrospective design of all the studies; (iii) the considerable heterogeneity for c-Met assessment, starting from technical issues up to the variability regarding the rates of high value of c-Met expression (range, 16.7–80%); (iv) the paucity of data in most studies [30].