Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer

  • Cancer Discov. 2016 Oct;6(10):1118-1133. doi: 10.1158/2159-8290.CD-16-0596.
Justin F Gainor  1 ,  Leila Dardaei  1 ,  Satoshi Yoda  1 ,  Luc Friboulet  2 ,  Ignaty Leshchiner  3 ,  Ryohei Katayama  4 ,  Ibiayi Dagogo-Jack  1 ,  Shirish Gadgeel  5 ,  Katherine Schultz  1 ,  Manrose Singh  1 ,  Emily Chin  1 ,  Melissa Parks  1 ,  Dana Lee  1 ,  Richard H DiCecca  1 ,  Elizabeth Lockerman  1 ,  Tiffany Huynh  6 ,  Jennifer Logan  1 ,  Lauren L Ritterhouse  6 ,  Long P Le  6 ,  Ashok Muniappan  7 ,  Subba Digumarthy  8 ,  Colleen Channick  1 ,  Colleen Keyes  1 ,  Gad Getz  3 ,  Dora Dias-Santagata  6 ,  Rebecca S Heist  1 ,  Jochen Lennerz  6 ,  Lecia V Sequist  1 ,  Cyril H Benes  1 ,  A John Iafrate  6 ,  Mari Mino-Kenudson  6 ,  Jeffrey A Engelman  9 ,  Alice T Shaw  9
Affiliations
  • 1. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
  • 2. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Gustave Roussy Cancer Campus, Université Paris Saclay, INSERM U981, Paris, France.
  • 3. Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
  • 4. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 5. Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
  • 6. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
  • 7. Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
  • 8. Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
  • 9. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. [email protected] [email protected].
PMID: 27432227 DOI: 10.1158/2159-8290.CD-16-0596
Abstract

Advanced, anaplastic lymphoma kinase (ALK)-positive Lung Cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Significance: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.

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