TY - JOUR
T1 - ALK fusion partners impact response to ALK inhibition
T2 - Differential effects on sensitivity, cellular phenotypes, and biochemical properties
AU - Childress, Merrida A.
AU - Himmelberg, Stephen M.
AU - Chen, Huiqin
AU - Deng, Wanleng
AU - Davies, Michael A.
AU - Lovly, Christine M.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/11
Y1 - 2018/11
N2 - Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 50 fusion partner genes have been reported, treatment of ALK-rearranged cancers is decided without regard to which 50 partner is present. There is little data addressing how the 50 partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKI). On the basis of the hypothesis that the 50 partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs, clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated. Biochemical and cellular assays were used to assess the efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. IC50s were calculated for different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and consistent differences (5-10 fold) in drug sensitivity were noted across the seven ALK fusions tested. Finally, biochemical analyses revealed negative correlations between kinase activity and protein stability. These results demonstrate that the 50 fusion partner plays an important biological role that affects sensitivity to ALK TKIs. Implications: This study shows that the 50 ALK fusion partner influences ALK TKI drug sensitivity. As many other kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies have ramifications for other kinase-driven malignancies.
AB - Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 50 fusion partner genes have been reported, treatment of ALK-rearranged cancers is decided without regard to which 50 partner is present. There is little data addressing how the 50 partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKI). On the basis of the hypothesis that the 50 partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs, clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated. Biochemical and cellular assays were used to assess the efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. IC50s were calculated for different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and consistent differences (5-10 fold) in drug sensitivity were noted across the seven ALK fusions tested. Finally, biochemical analyses revealed negative correlations between kinase activity and protein stability. These results demonstrate that the 50 fusion partner plays an important biological role that affects sensitivity to ALK TKIs. Implications: This study shows that the 50 ALK fusion partner influences ALK TKI drug sensitivity. As many other kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies have ramifications for other kinase-driven malignancies.
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U2 - 10.1158/1541-7786.MCR-18-0171
DO - 10.1158/1541-7786.MCR-18-0171
M3 - Article
C2 - 30002191
AN - SCOPUS:85053442176
SN - 1541-7786
VL - 16
SP - 1724
EP - 1736
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 11
ER -