title: RAS-MAPK in ALK targeted therapy resistance.
abstract: The clinical success of ALK targeted therapy is limited by resistance. To identify rational co-targeting strategies to enhance clinical outcomes, we explored the molecular basis of ALK oncogene dependence in ALK gene rearrangement positive (ALK+) lung adenocarcinoma. We discovered that the RAS-RAF-MEK-ERK pathway is the critical downstream pathway necessary for ALK+ tumor cell survival. Upfront co-targeting of ALK plus MEK enhanced response and forestalled resistance in preclinical ALK+ tumor models, providing rationale for a new approach the treatment of ALK+ patients.
authors.affiliation: a Department of Medicine ; University of California at San Francisco ; San Francisco , CA USA.|b Helen Diller Family Comprehensive Cancer Center; University of California at San Francisco ; San Francisco , CA USA.
authors.forename: Gorjan
authors.initials: G
authors.lastname: Hrustanovic
authors.affiliation: a Department of Medicine ; University of California at San Francisco ; San Francisco , CA USA.|b Helen Diller Family Comprehensive Cancer Center; University of California at San Francisco ; San Francisco , CA USA.
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000628:therapy; D000077192:Adenocarcinoma of Lung; D000077548:Anaplastic Lymphoma Kinase; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins
keywords: ALK; MAPK; MEK; RAS; lung cancer; polytherapy; resistance