Investigation of EGFR Inter-domain Relations and Their Roles in Lung Cancer Drug Resistance
DescriptionLung cancer has the highest mortality rate among all cancer types and results in over a million deaths in the world yearly. Around 85% of lung cancer patients have non-small cell lung cancer (NSCLC). A major cause of NSCLC is the mutation of a protein called the epidermal growth factor receptor (EGFR) in the tyrosine kinase (TK) domain. The first generation drugs, reversible EGFR TK inhibitors (TKIs), are effective initially for treating NSCLC, but almost all patients develop drug resistance after a period of time due to another EGFR mutation. Although recent second and third generation drugs are more effective, drug resistance can still occur, for example, through the activation of a downstream signaling pathway.We have made significant contributions to the analysis of NSCLC drug resistance. We have close collaborations with a genomics technology company and medical doctors at HKU and Queen Mary Hospital. Our research results have already been used by industry and in clinical work. However, our past work focused on EGFR mutants and the TK domain only. This project will address a much more challenging problem, how EGFR related proteins form homodimers and heterodimers and interact with each other, causing resistance even to new generations of drugs through downstream pathways.EGFR is a multi-domain protein and performs its biological functions through various dimerizations. The dimers can be formed due to interactions in different domains. Thus, it is important to investigate how mutations in the TK domain affect functions in other domains. We will develop advanced parametric spectral analysis, projection onto convex sets and probabilistic relaxation labeling based algorithms to identify interactions between EGFR and other proteins. The molecular dynamics data will be treated as non- stationary signals and tensor models will be employed to find the inter-domain relations. We will investigate the structural changes in different domains of EGFR for all known mutations that cause lung cancer and drug resistance. How these changes affect the dimer formation and influence the activities in related signaling pathways will be elucidated. We will study the possibility of targeting one or more proteins in the affected pathways to tackle the drug resistance problem.Through our research work, we can achieve a deep understanding of the drug resistance problem in NSCLC treatment. In addition to scientific contributions to a cutting-edge research area, this project will deliver powerful tools to medical doctors for personalized treatment of lung cancer patients and bring significant benefits to the society.
|Effective start/end date||1/01/19 → …|