title: Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors.
abstract: Selective kinase inhibitors have had a substantial impact on the field of medical oncology. Whereas these agents can elicit dramatic clinical responses in some settings, their activity is generally limited to a subset of treated patients whose tumor cells harbor a specific genetic lesion. We have established an automated platform for examining the sensitivity to various molecularly targeted inhibitors across a large panel of human tumor-derived cell lines to identify additional genotype-correlated responses that may be clinically relevant. Among the inhibitors tested in a panel of 602 cell lines derived from a variety of human cancers, we found that a selective inhibitor of the anaplastic lymphoma kinase (ALK) potently suppressed growth of a small subset of tumor cells. This subset included lines derived from anaplastic large cell lymphomas, non-small-cell lung cancers, and neuroblastomas. ALK is a receptor tyrosine kinase that was first identified as part of a protein fusion derived from a chromosomal translocation detected in the majority of anaplastic large cell lymphoma patients, and has recently been implicated as an oncogene in a small fraction of non-small-cell lung cancers and neuroblastomas. Significantly, sensitivity in these cell lines was well correlated with specific ALK genomic rearrangements, including chromosomal translocations and gene amplification. Moreover, in such cell lines, ALK kinase inhibition can lead to potent suppression of downstream survival signaling and an apoptotic response. These findings suggest that a subset of lung cancers, lymphomas, and neuroblastomas that harbor genomic ALK alterations may be clinically responsive to pharmacologic ALK inhibition.
authors.affiliation: Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.forename: Marie
authors.initials: M
authors.lastname: Classon
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Smith
authors.forename: Lori
authors.initials: L
authors.lastname: Dowell
authors.forename: Lindsey E
authors.initials: LE
authors.lastname: Ulkus
authors.forename: Georgiana
authors.initials: G
authors.lastname: Kuhlmann
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D020732:Cytogenetic Analysis; D004353:Drug Evaluation, Preclinical; D005784:Gene Amplification / Q000502:physiology; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D008223:Lymphoma / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D009447:Neuroblastoma / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011728:Pyridones / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; C504983:BMS 536924; D001562:Benzimidazoles; C516714:NVP-TAE684; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases