2. Academic Validation
  3. Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

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

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. jjlin1@partners.org.
  • 8 Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. jjlin1@partners.org.
  • 9 Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. syoda@mgh.harvard.edu.
  • 10 Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. syoda@mgh.harvard.edu.
  • 11 Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. ahata@mgh.harvard.edu.
  • 12 Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ahata@mgh.harvard.edu.
  • # 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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