Structure and energy based quantitative missense variant effect analysis provides insights into drug resistance mechanisms of anaplastic lymphoma kinase mutations

Scientific Reports
Jianzong LiJinku Bao

Abstract

Anaplastic lymphoma kinase (ALK) is considered as a validated molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the effectiveness of molecularly targeted therapies using ALK inhibitors is almost universally limited by drug resistance. Drug resistance to molecularly targeted therapies has now become a major obstacle to effective cancer treatment and personalized medicine. It is of particular importance to provide an improved understanding on the mechanisms of resistance of ALK inhibitors, thus rational new therapeutic strategies can be developed to combat resistance. We used state-of-the-art computational approaches to systematically explore the mutational effects of ALK mutations on drug resistance properties. We found the activation of ALK was increased by substitution with destabilizing mutations, creating the capacity to confer drug resistance to inhibitors. In addition, results implied that evolutionary constraints might affect the drug resistance properties. Moreover, an extensive profile of drugs against ALK mutations was constructed to give better understanding of the mechanism of drug resistance based on structural transitions and energetic variation. Our work hopes to provi...Continue Reading

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Methods Mentioned

BETA
PCA

Software Mentioned

Evmutation
MM
AmberTools
PBSA
PyMOL
FoldX
plmc
FreeSASA
GROMACS
GBSA

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