Genomic and experimental evidence that ALK^ATI does not predict single agent sensitivity to ALK inhibitors

Genomic data can facilitate personalized treatment decisions by enabling therapeutic hypotheses in individual patients. Mutual exclusivity has been an empirically useful signal for identifying activating mutations that respond to single agent targeted therapies. However, a low mutation frequency can underpower this signal for rare variants. We develop a resampling based method for the direct pairwise comparison of conditional selection between sets of gene pairs. We apply this method to a transcript variant of anaplastic lymphoma kinase (ALK) in melanoma, termed ALK^ATI that was suggested to predict sensitivity to ALK inhibitors and we find that it is not mutually exclusive with key melanoma oncogenes. Furthermore, we find that ALK^ATI is not likely to be sufficient for cellular transformation or growth, and it does not predict single agent therapeutic dependency. Our work strongly disfavors the role of ALK^ATI as a targetable oncogenic driver that might be sensitive to single agent ALK treatment.