EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

Abstract

EGFR and c-Met are receptor tyrosine kinases that are implicated in tumor development and progression in several types of cancer. Both EGFR and c-Met, which are known to be overexpressed and mutated in cancer, share common signaling pathways, including the PI3K/ Akt and MAPK pathways. Small molecule tyrosine kinase inhibitors and monoclonal antibodies that work against EGFR and c-Met are at the forefront of cancer therapy, but their individual efficacies are limited due to the development of drug resistance. In recent pre-clinical studies, we observed that combination therapy using mTOR and Wnt inhibitors with EGFR or c-Met tyrosine kinase inhibitors resulted in overcoming drug resistance. Our studies also indicated that EGFR and c-Met tyrosine kinase inhibitor resistance may be due to activation of alternative signaling pathways. The development of additional combinatorial therapies is underway, and various combinations of inhibitors have shown promising results in clinical trials. Future studies in this direction could be the basis for development of new cancer therapeutics, utilizing EGFR and c-Met inhibitors, which could greatly improve patient prognosis.

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

“…The synergistic regulation of signaling mediated by ERBB1 and c-MET receptors is important in the regulation of cancer progression, metastasis, and drug resistance [ 16 , 28 , 30 ]. The downstream protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK) are co-regulated by both ERBB1 and c-MET receptors [ 31 ].…”

“…Recent clinical studies with small molecule inhibitors, including tyrosine kinase inhibitors, anti-ERBB2 agents, PI3K/Akt/mTOR inhibitors, and CDK4/6 inhibitors, have shown promise in inhibiting proliferation and metastasis in ERBB2 + BC [ 10 , 11 , 12 ]. For instance, inhibitors targeting ERBB1 and c-MET receptors that are upregulated during BC metastasis, are currently being investigated in clinical trials for patients with existing metastasis [ 13 , 14 , 15 , 16 ]. Neratinib (NER), an irreversible pan-ERBB family inhibitor, has been reported to be efficacious in metastatic BC patients in combination with capecitabine [ 17 ] and paclitaxel [ 18 , 19 ].…”

A Perspective on Covalent Inhibitors: Research and Development Trends of Warheads and Targets

“…117 Erlotinib, gefitinib, and lapatinib are reversible non-covalent tyrosine kinase inhibitors (TKIs), which have been approved for the treatment of NSCLC and HER2 receptor positive breast cancer patients. [118][119][120] However, kinases have acquired resistance to the reversible TKIs over time. To circumvent resistance, second generation TKIscovalent inhibitors were strategically designed with acrylamide Michael acceptors to react with the cysteine residue (Cys797) in EGFR.…”

The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 ‘CREATE’

“…Crizotinib interferes with the ALK/MET pathways by competitively preventing adenosine triphosphate (ATP) from binding to the ALK and MET receptors, therefore abrogating their phosphorylation [27][28][29][30][31]. This blocks the downstream cascade of events, thereby inhibiting the growth and survival of ALK or MET dependent cells [27][28][29][30][31][32][33][34]. Crizotinib is approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumours are either ALK or ROS1 positive, and the recommended oral dose in adult patients is 250mg twice daily [29,30].…”