ALK mutations conferring differential resistance to structurally diverse ALK inhibitors
Menée in vitro sur des lignées cellulaires de cancer du poumon présentant une fusion des gènes EML4 et ALK, cette étude identifie des mutations associées à l'apparition d'une résistance au crizotinib et à une autre molécule inhibitrice d'ALK, TAE684
Purpose: EML4-ALK fusions define a subset of lung cancers that can be effectively treated with ALK kinase 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 diamino-pyrimidine TAE684 Results: Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L, G1269S), are highly sensitive to the structurally unrelated ALK kinase inhibitor TAE684. In addition, we identified two novel EML4-ALK resistance mutations (L1198P and D1203N) which unlike previously reported mutations induced resistance to both ALK kinase inhibitors. An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684, but not to PF02341066. Conclusions: Our results demonstrate that different ALK resistance mutations as well as different ALK inhibitors impact the therapeutic efficacy in the setting of EML4-ALK fusions and ALK mutations.