Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F

Alice T Shaw; Luc Friboulet; Ignaty Leshchiner; Justin F Gainor; Simon Bergqvist; Alexei Brooun; Benjamin J Burke; Ya-Li Deng; Wei Liu; Leila Dardaei; Rosa L Frias; Kate R Schultz; Jennifer Logan; Leonard P James; Tod Smeal; Sergei Timofeevski; Ryohei Katayama; A John Iafrate; Long Le; Michele McTigue; Gad Getz; Ted W Johnson; Jeffrey A Engelman

doi:10.1056/NEJMoa1508887

Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F

N Engl J Med. 2016 Jan 7;374(1):54-61. doi: 10.1056/NEJMoa1508887. Epub 2015 Dec 23.

Authors

Alice T Shaw¹, Luc Friboulet¹, Ignaty Leshchiner¹, Justin F Gainor¹, Simon Bergqvist¹, Alexei Brooun¹, Benjamin J Burke¹, Ya-Li Deng¹, Wei Liu¹, Leila Dardaei¹, Rosa L Frias¹, Kate R Schultz¹, Jennifer Logan¹, Leonard P James¹, Tod Smeal¹, Sergei Timofeevski¹, Ryohei Katayama¹, A John Iafrate¹, Long Le¹, Michele McTigue¹, Gad Getz¹, Ted W Johnson^#¹, Jeffrey A Engelman^#¹

Affiliation

¹ Massachusetts General Hospital Cancer Center (A.T.S., L.F., J.F.G., L.D., R.L.F., K.R.S., J.L., G.G., J.A.E.) and the Department of Pathology (A.J.I., L.L., G.G.), Massachusetts General Hospital, Boston, and the Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge (I.L., G.G.) - all in Massachusetts; Pfizer Worldwide Research and Development, La Jolla, CA (S.B., A.B., B.J.B., Y.-L.D., W.L., L.P.J., T.S., S.T., M.M., T.W.J.); and the Japanese Foundation for Cancer Research, Tokyo (R.K.).

^# Contributed equally.

Abstract

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

Publication types

Case Reports
Clinical Trial, Phase I
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines
Anaplastic Lymphoma Kinase
Binding Sites
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / secondary
Crizotinib
Drug Resistance, Neoplasm / genetics*
Female
Humans
Lactams
Lactams, Macrocyclic / therapeutic use*
Liver Failure / etiology
Liver Neoplasms / secondary
Lung Neoplasms / drug therapy*
Lung Neoplasms / genetics
Middle Aged
Molecular Structure
Mutation*
Protein Kinase Inhibitors / therapeutic use*
Pyrazoles / therapeutic use*
Pyridines / therapeutic use*
Pyrimidines / therapeutic use
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / genetics*
Sulfones / therapeutic use

Substances

Aminopyridines
Lactams
Lactams, Macrocyclic
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Pyrimidines
Sulfones
Crizotinib
ALK protein, human
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases
ceritinib
lorlatinib

Associated data

ClinicalTrials.gov/NCT01970865

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding