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.
Aya Shiba-Ishii   #  1 ,  Ted W Johnson   #  2 ,  Ibiayi Dagogo-Jack  1  3 ,  Mari Mino-Kenudson  1  4  5 ,  Theodore R Johnson  2 ,  Ping Wei  2 ,  Scott L Weinrich  2 ,  Michele A McTigue  2 ,  Makeba A Walcott  1 ,  Linh Nguyen-Phuong  1 ,  Kristin Dionne  1 ,  Adam Acker  1 ,  Lesli A Kiedrowski  6 ,  Andrew Do  1  3 ,  Jennifer L Peterson  1  3 ,  Jaimie L Barth  4 ,  Beow Y Yeap  1  3 ,  Justin F Gainor  1  3 ,  Jessica J Lin  7  8 ,  Satoshi Yoda  9  10 ,  Aaron N Hata  11  12
Affiliations
  • 1. Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
  • 2. Pfizer Worldwide Research and Development, La Jolla, CA, USA.
  • 3. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 4. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • 5. Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • 6. Guardant Health, Redwood City, CA, USA.
  • 7. Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. [email protected].
  • 8. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
  • 9. Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. [email protected].
  • 10. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
  • 11. Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. [email protected].
  • 12. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 35726063 DOI: 10.1038/s43018-022-00399-6
Abstract

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.

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