Making NSCLC Crystal Clear: How Kinase Structures Revolutionized Lung Cancer Treatment

Juliana F. Vilacha*, Sarah C. Mitchel, Muluembet Z. Akele, Stephen Evans, Matthew R. Groves*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)
117 Downloads (Pure)

Abstract

The parallel advances of different scientific fields provide a contemporary scenario where collaboration is not a differential, but actually a requirement. In this context, crystallography has had a major contribution on the medical sciences, providing a "face" for targets of diseases that previously were known solely by name or sequence. Worldwide, cancer still leads the number of annual deaths, with 9.6 million associated deaths, with a major contribution from lung cancer and its 1.7 million deaths. Since the relationship between cancer and kinases was unraveled, these proteins have been extensively explored and became associated with drugs that later attained blockbuster status. Crystallographic structures of kinases related to lung cancer and their developed and marketed drugs provided insight on their conformation in the absence or presence of small molecules. Notwithstanding, these structures were also of service once the initially highly successful drugs started to lose their effectiveness in the emergence of mutations. This review focuses on a subclassification of lung cancer, non-small cell lung cancer (NSCLC), and major oncogenic driver mutations in kinases, and how crystallographic structures can be used, not only to provide awareness of the function and inhibition of these mutations, but also how these structures can be used in further computational studies aiming at addressing these novel mutations in the field of personalized medicine.

Original languageEnglish
Article number725
Pages (from-to)1-52
Number of pages52
JournalCrystals
Volume10
Issue number9
DOIs
Publication statusPublished - Sept-2020

Keywords

  • cancer
  • NSCLC
  • mutation
  • kinase
  • EGFR
  • KRAS
  • ALK
  • BRAF
  • personalized medicine
  • molecular modeling
  • EPIDERMAL-GROWTH-FACTOR
  • ANAPLASTIC LYMPHOMA KINASE
  • RECEPTOR TYROSINE KINASE
  • EML4-ALK FUSION GENE
  • MOLECULAR-DYNAMICS SIMULATIONS
  • 2ND-GENERATION ALK INHIBITORS
  • MUTATION CONFERS RESISTANCE
  • FREE-ENERGY PERTURBATION
  • TARGETING RAF KINASE
  • ONCOGENIC K-RAS

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