Methods of treating non-small cell lung carcinoma (NSCLC)

摘要

Novel gene deletions and translocations involving chromosome 2 resulting in fusion proteins combining part of Anaplastic Lymphoma Kinase (ALK) kinase with part of a secondary protein have been identified herein in human solid tumors, e.g. non-small cell lung carcinoma (NSCLC). Secondary proteins include Echinoderm Microtubule-Associated Protein-Like 4 (EML-4) and TRK-Fusion Gene (TFG). The EML4-ALK fusion protein, which retains ALK tyrosine kinase activity, was confirmed to drive the proliferation and survival of NSCLC characterized by this mutation. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant ALK kinase polypeptides, probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The disclosed identification of this new fusion protein enables methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides.

主权项

1. A method for treating a human subject having a non-small cell lung carcinoma (NSCLC) that expresses a human Echinoderm Microtubule-Associated Protein-Like 4 (EML4)-Anaplastic Lymphoma Kinase (ALK) fusion polypeptide, comprising
administering to the human subject a small molecule that a) binds to the ATP-binding cleft and b) directly inhibits the kinase activity of the EML4-ALK fusion polypeptide, in an amount effective to treat the NSCLC, wherein i) the EML4-ALK fusion polypeptide comprises an amino acid sequence that is at least 95% identical to an amino acid sequence comprising EML4 amino acid residues 1-222 of SEQ ID NO: 3 and ALK amino acid residues 1116-1383 of SEQ ID NO: 5 and ii) the EML4 amino acid residues are amino-terminal to the ALK amino acid residues.