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Significance High-risk tumors are genomically heterogeneous, harboring gene amplifications and mutations. The activation status of mutated proteins in cancer can profoundly impact disease progression, patient response, and drug sensitivity. Yet, outside of a few hotspot mutations, functional studies of clinically observed mutations are not commonly pursued. We report a combined experimental profiling and computational analysis of the effects of clinically observed and “test” mutations in the kinase domain of anaplastic lymphoma kinase (ALK), a known oncogenic driver in pediatric neuroblastoma. We find that the activation status of the mutated protein is a good indicator of the transforming ability in NIH 3T3 cells. We also report biophysical as well as data-driven models with predictive power to profile these mutant kinases in silico.

Computational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation