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Computational Investigation and Experimental Validation of Crizotinib Resistance Conferred by C1156Y Mutant
Anish Kumar1, V Shanthi1, K Ramanathan2
1Industrial Biotechnology Division, School of Bio Sciences and Technology, VIT University, Vellore - 632014, Tamil Nadu, India tel: +91 4162202608; fax: +91 4162243092.
Abstract:
Crizotinib is an anticancer drug approved by FDA for the treatment of non-small cell lung cancer (NSCLC). The main target for crizotinib was anaplastic lymphoma kinase (ALK). However, evidences available indicate that C1156Y mutation in ALK confers resistance to crizotinib. Unfortunately, how mutation actually confers drug resistance is not well understood. Hence, in the present study computational approaches have been employed alongside KINOMEscan profiling technique to reveal the mechanism behind crizotinib resistance in ALK at a molecular level. The results of our analysis indicate that C1156Y mutation alters the conformation of the ALK binding pocket residues which results in a marked decrease in hydrogen bond interactions between crizotinib and ALK. This indicates that hydrogen bonding was a crucial effector of decreased binding affinity. Interestingly, the docking study also indicates that C1156Y mutation increases the affinity for ATP. Finally, our analysis theoretically suggests that M-1199 is a key residue responsible for the ALK drug selectivity. We certainly believe that these results may be immense importance for the molecular level understanding of crizotinib resistance pattern and also for designing a potential drug molecule for the treatment of lung cancer in the near future.
Insights
The C1156Y mutation in anaplastic lymphoma kinase (ALK) reduces crizotinib effectiveness by altering binding. This resistance mechanism involves decreased hydrogen bonds and increased ATP affinity, impacting non-small cell lung cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- Crizotinib is an FDA-approved drug for non-small cell lung cancer (NSCLC) targeting anaplastic lymphoma kinase (ALK).
- The C1156Y mutation in ALK is known to confer resistance to crizotinib, but the underlying molecular mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanism of crizotinib resistance mediated by the ALK C1156Y mutation.
- To investigate the impact of the C1156Y mutation on the binding affinity and interactions between crizotinib and ALK.
Main Methods:
- Employed computational approaches, including molecular docking simulations.
- Utilized KINOMEscan profiling to assess kinase activity and binding.
- Analyzed changes in the ALK binding pocket conformation and hydrogen bonding interactions.
Main Results:
- The C1156Y mutation significantly alters the ALK binding pocket conformation, reducing hydrogen bond interactions with crizotinib.
- Hydrogen bonding is identified as a critical factor in the decreased binding affinity of crizotinib to mutated ALK.
- Docking studies revealed that the C1156Y mutation enhances the affinity of ALK for ATP.
- The M-1199 residue is theoretically identified as crucial for ALK's drug selectivity.
Conclusions:
- The C1156Y mutation confers crizotinib resistance by disrupting key hydrogen bonds and increasing ATP affinity.
- Understanding these molecular alterations is vital for developing new therapeutic strategies for lung cancer.
- The findings provide a basis for designing novel ALK inhibitors to overcome resistance in NSCLC treatment.
