Life Sciences & Biotechnology
Title : | Deciphering molecular signatures for resistance to some kinase inhibitors used in the treatment of non-small cell lung cancer (NsCLC):A bioinformatics approach |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Om silakari, Punjabi University, Punjab |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | omsilakari@gmail.com |
Details
Executive Summary : | Lung cancer remains a leading cause of cancer-related mortality, with conventional cytotoxic chemotherapies being limited in their effectiveness. The disease is marked by altered EGFR and fusions involving ALK and other receptor tyrosine kinases (RTKs). Kinases remain the most effective molecular target in NsCLC therapy, but resistance mechanisms, such as mutations in EGFR T790M and amplification of the MET oncogene, limit their effectiveness. Around 50% of patients with acquired resistance show a secondary gatekeeper mutation, EGFR T790M. Other secondary mutations involved in acquired resistance include D761Y, L747s, and T854A. Amplification of c-MET has been a major mechanism of resistance in EGFR overexpressed patients, and simultaneous overexpression of c-MET in previously secondary acquired EGFR T790M worsens the situation. Current approaches for managing resistant NsCLC involve developing third-generation kinase inhibitors, dual inhibitors, and specific targeting T790M EGFR along with HsP90 inhibitors. However, recent disclosure of the C797s mutation against covalent inhibitors suggests the near future failure of covalent inhibitors. Deciphering molecular signatures for secondary acquired mutation and amplification of parallel signaling pathways (c-MET, Erbb2, AXL) responsible for resistance to some clinically approved kinase inhibitors for NsCLC is crucial for designing inhibitors that may block T790M specific EGFR along with other kinases involved in NsCLC. Planned treatment designing using bioinformatics approaches coupled with computational tools could provide rational and cost-effective development of novel therapeutics for NsCLC treatment. |
Total Budget (INR): | 18,00,830 |
Organizations involved