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Genomic and experimental evidence that ALKATI does not predict single agent sensitivity to ALK inhibitors.

ABSTRACT: 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 ALKATI 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 ALKATI 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 ALKATI as a targetable oncogenic driver that might be sensitive to single agent ALK treatment.

SUBMITTER: Inam H 

PROVIDER: S-EPMC8603052 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Genomic and experimental evidence that ALK<sup>ATI</sup> does not predict single agent sensitivity to ALK inhibitors.

Inam Haider H   Sokirniy Ivan I   Rao Yiyun Y   Shah Anushka A   Naeemikia Farnaz F   O'Brien Edward E   Dong Cheng C   McCandlish David M DM   Pritchard Justin R JR  

iScience 20211026 11

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 transc  ...[more]

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