Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

Nat Cancer. 2022 Jun;3(6):710-722. doi: 10.1038/s43018-022-00399-6. Epub 2022 Jun 20.


Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminopyridines
  • Anaplastic Lymphoma Kinase / genetics
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Lactams
  • Lactams, Macrocyclic / pharmacology
  • Lung Neoplasms* / drug therapy
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles


  • Aminopyridines
  • Lactams
  • Lactams, Macrocyclic
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Anaplastic Lymphoma Kinase
  • lorlatinib