ALK mutations conferring differential resistance to structurally diverse ALK inhibitors.

ABSTRACT:

Purpose

EML4-ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration of response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, a better understanding of resistance mechanisms will help to enhance tumor control in EML4-ALK-positive tumors.

Experimental design

By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684.

Results

Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L and G1269S), are highly sensitive to the structurally unrelated ALK inhibit

SUBMITTER: Heuckmann JM 

PROVIDER: S-EPMC3382103 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature