ISS1-2-4 - An activating ALK gene mutation in ALK IHC-positive/FISH-negative non-small cell lung cancer

Abstract

Backgrounds ALK inhibitors (i.e. crizotinib and alectinib) have shown marked antitumor activity against non-small cell lung cancer (NSCLC) with ALK rearrangements. Detection of ALK rearrangements is mainly performed by fluorescence in-situ hybridization (FISH). However, these can yield false-positive and false-negative results.Methods and results: We discovered an ALK kinase domain mutation in ALK immunohistochemistry (IHC)-positive but FISH-negative NSCLC. ALK was phosphorylated when this mutation was overexpressed in HEK293 cell line. Focus formation and a tumorigenicity assays with the NIH-3T3 cell lines and nude mice showed that this mutation had the transformational ability and enhanced tumorigenicity, compared with controls. The ALK mutation-overexpressed Ba/F3 cell line showed IL-3-independent growth and was sensitive to ALK inhibitors.Conclusion: Lung cancer ALK IHC-positive/FISH-negative may have activating ALK mutations. Although this population may be small, these patients can benefit form ALK inhibitors. Further comprehensive analyses should be introduced into clinical setting in order to identify these cases. Backgrounds ALK inhibitors (i.e. crizotinib and alectinib) have shown marked antitumor activity against non-small cell lung cancer (NSCLC) with ALK rearrangements. Detection of ALK rearrangements is mainly performed by fluorescence in-situ hybridization (FISH). However, these can yield false-positive and false-negative results. Methods and results: We discovered an ALK kinase domain mutation in ALK immunohistochemistry (IHC)-positive but FISH-negative NSCLC. ALK was phosphorylated when this mutation was overexpressed in HEK293 cell line. Focus formation and a tumorigenicity assays with the NIH-3T3 cell lines and nude mice showed that this mutation had the transformational ability and enhanced tumorigenicity, compared with controls. The ALK mutation-overexpressed Ba/F3 cell line showed IL-3-independent growth and was sensitive to ALK inhibitors. Conclusion: Lung cancer ALK IHC-positive/FISH-negative may have activating ALK mutations. Although this population may be small, these patients can benefit form ALK inhibitors. Further comprehensive analyses should be introduced into clinical setting in order to identify these cases.