2. Academic Validation
  3. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer

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

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. ashaw1@partners.org jeffrey.engelman@novartis.com.
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.

Figures
Products