Abstract
The success of ALK targeted therapy is blunted by resistance. To identify rational polytherapy strategies to improve clinical outcomes, we studied the molecular basis of ALK oncogene dependence in ALK gene rearrangement positive (ALK+) lung adenocarcinoma. We discovered that RAS-RAF-MEK-ERK signaling is the crucial downstream pathway that is required for ALK+ tumor cell survival. Upfront co-inhibition of ALK and MEK improved response and blocked resistance in preclinical ALK+ lung cancer models, providing rationale for a new treatment paradigm for ALK+ patients.
Keywords:
ALK; MAPK; MEK; RAS; lung cancer; polytherapy; resistance.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / genetics*
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Adenocarcinoma of Lung
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Anaplastic Lymphoma Kinase
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Drug Resistance, Neoplasm
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics*
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MAP Kinase Signaling System / drug effects
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Oncogene Proteins, Fusion / genetics*
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics*
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Translational Research, Biomedical
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ras Proteins / metabolism
Substances
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Oncogene Proteins, Fusion
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Protein Kinase Inhibitors
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ALK protein, human
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases
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Mitogen-Activated Protein Kinase Kinases
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ras Proteins