title: A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.
abstract: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Jussi
authors.initials: J
authors.lastname: Koivunen
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ogino
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yanagita
authors.forename: Sarah
authors.initials: S
authors.lastname: Nikiforow
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Christopher
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authors.lastname: Lathan
authors.forename: J Paul
authors.initials: JP
authors.lastname: Marcoux
authors.forename: Jinyan
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authors.lastname: Du
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Okuda
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.forename: Magda
authors.initials: M
authors.lastname: Stumpfova
authors.forename: Yun
authors.initials: Y
authors.lastname: Xiao
authors.forename: Stanislawa
authors.initials: S
authors.lastname: Weremowicz
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Stephanie
authors.initials: S
authors.lastname: Heon
authors.forename: Keith
authors.initials: K
authors.lastname: Wilner
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Neal
authors.initials: N
authors.lastname: Lindeman
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases