title: Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.
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.).
authors.affiliation: 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.).
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: 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.).
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.affiliation: 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.).
authors.forename: Ignaty
authors.initials: I
authors.lastname: Leshchiner
authors.affiliation: 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.).
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.affiliation: 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.).
authors.forename: Simon
authors.initials: S
authors.lastname: Bergqvist
authors.affiliation: 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.).
authors.forename: Alexei
authors.initials: A
authors.lastname: Brooun
authors.affiliation: 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.).
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burke
authors.affiliation: 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.).
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Deng
authors.affiliation: 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.).
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: 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.).
authors.forename: Leila
authors.initials: L
authors.lastname: Dardaei
authors.affiliation: 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.).
authors.forename: Rosa L
authors.initials: RL
authors.lastname: Frias
authors.affiliation: 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.).
authors.forename: Kate R
authors.initials: KR
authors.lastname: Schultz
authors.affiliation: 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.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Logan
authors.affiliation: 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.).
authors.forename: Leonard P
authors.initials: LP
authors.lastname: James
authors.affiliation: 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.).
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
authors.affiliation: 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.).
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.affiliation: 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.).
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.affiliation: 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.).
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: 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.).
authors.forename: Long
authors.initials: L
authors.lastname: Le
authors.affiliation: 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.).
authors.forename: Michele
authors.initials: M
authors.lastname: McTigue
authors.affiliation: 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.).
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: 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.).
authors.forename: Ted W
authors.initials: TW
authors.lastname: Johnson
authors.affiliation: 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.).
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D017093:Liver Failure / Q000209:etiology; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D013450:Sulfones / Q000627:therapeutic use
chemical_list: D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib; C000590786:lorlatinib