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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
Interestingly, while the efficacy of crizotinib in ALK-positive NSCLC is well established [4], it was initially developed as a potent MET inhibitor [59]. Ou et al. described a case of ALK negative but MET amplified stage IV adenocarcinoma of lung where crizotinib was used after the progression of disease on chemotherapy with an excellent partial response and a progression-free interval of at least six months [60]. In another case, crizotinib was used after radiation in c-MET amplified squamous cell lung cancer with significant partial response for at least eight weeks [61]. In an ongoing phase 1 study (NCT00585195), crizotinib was reported to have some antitumor activity in patients with c-Met-amplified NSCLC, with the response rate as high as 50% in the subgroup with high MET/CEP7 ratio [62].
Hepatocellular Carcinoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
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 (HGF) signaling 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 tivantinib has been investigated in a randomized phase II trial for patients with HCC and significantly prolonged time to progression, the primary endpoint of the study, compared with best supportive care (HR 0.64). An exploratory analysis of survival according to c-met expression assessed by immunohistochemistry on tumor biopsies suggested that c-met was an adverse prognostic factor and that patients with high c-met may derive greatest benefit.94 However, a prospective phase III trial enrolling patients with high c-met expression failed to demonstrate a survival benefit in this population.95 Conversely, a phase III placebo-controlled trial of cabozantinib, which also inhibits c-met (as well as other targets), did demonstrate a survival benefit in patients previously treated with anti-angiogenic drugs (largely sorafenib) without any biomarker selection.96
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
An updated patent review of small-molecule c-Met kinase inhibitors (2018-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Cilong Chu, Zixuan Rao, Qingshan Pan, Wufu Zhu
Small molecule inhibitors of c-Met have flourished over the decades and many inhibitors have entered the clinical phase or even been marketed. Based on the structural features of the inhibitors and their mode of binding to kinases, c-Met inhibitors are divided into three categories. Type I: ATP-competitive inhibitors, which bind to proteins in a U-shaped structure, represented by the compound Crizotinib [23]. Type II: An ATP competitive multi-target inhibitor. These inhibitors bind to their targets in a more extended conformation and have a higher molecular weight and lipophilicity. This type of inhibitor is usually divided into four parts and has two distinctive features: one is a five-atom bridge linker structure containing six chemical bonds; the other feature is that the linker contains hydrogen, oxygen and nitrogen atoms that can form either a hydrogen bond donor or an acceptor, as represented by the compound Cabozantinib [24]. Type III: non-ATP competitive inhibitor, representative compound Tivantinib (clinical phase I). This review also collects the latest clinical c-Met inhibitors, including treatment type, clinical situation and action mechanism [25] (Table 1). The structures of some inhibitors are shown in Figure 2
Targets for MAbs: innovative approaches for their discovery & validation, LabEx MAbImprove 6th antibody industrial symposium, June 25-26, 2018, Montpellier, France
Published in mAbs, 2019
Pierre Martineau, Hervé Watier, Andre Pèlegrin, Andrei Turtoi
cMet. The anti-tumor activity of c-Met inhibitors is generally limited to tumors that are MET-activated and driven predominately by c-Met signaling. Telisotuzumab vedotin (ABBV-399), a c-Met targeting ADC, represents a novel therapeutic delivering a potent payload to c-Met–overexpressing tumor cells, enabling cell killing regardless of reliance on MET signaling. ABBV-399 treatment, alone and in combination with standard-of-care chemotherapy, induces significant tumor growth inhibition and regressions in tumor cell lines and patient-derived xenograft models with overexpressed c-Met or amplified MET, including tumors refractory to other c-Met inhibitors. ABBV-399 killing requires a threshold level of c-Met, expressed by sensitive tumor but not normal cells. ABBV-399 may be an effective broad-acting c-Met–targeting therapeutic that can overcome limitations associated with other c-Met inhibitors. ABBV-399 has progressed to a Phase 1 study where it has been well tolerated and has produced objective responses in c-Met–expressing NSCLC patients,14 and it is currently being investigated in a Phase 2 trial (NCT03539536).
c-Met kinase inhibitors: an update patent review (2014-2017)
Published in Expert Opinion on Therapeutic Patents, 2019
Qing-Wen Zhang, Zi-Dan Ye, Lei Shi
Several small molecule c-Met inhibitors have been developed over the past few decades. Two multi-target c-Met kinase inhibitors, crizotinib and cabozantinib, have been approved by the FDA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) and advanced renal cell carcinoma, respectively. In addition, there are a number of new targeted compounds currently undergoing clinical or preclinical testing to demonstrate their safety and efficacy. Some active clinical trials about novel agents targeting the pathway are summarized in Table 1. Their structures are in Figure 2. Some current c-Met inhibitors are found with resistance in cancer therapy now, so new compounds with novel structures need to be developed. In this review, most of these presented represented compounds with novel structures also exhibited good inhibitory activity on c-Met with IC50 less than 50 nM.