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

Inam, H, Sokirniy, I, Rao, Y, Shah, A, Naeemikia, F, O'Brien, E, Dong, C, McCandlish, DM, Pritchard, JR (November 2021) Genomic and experimental evidence that ALK<sup>ATI</sup> does not predict single agent sensitivity to ALK inhibitors. iScience, 24 (11). p. 103343. ISSN 2589-0042

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DOI: 10.1016/j.isci.2021.103343


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.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > melanomas
bioinformatics > genomics and proteomics > personal genomes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes > personal genomes
CSHL Authors:
Communities: CSHL labs > McCandlish lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 19 November 2021
Date Deposited: 06 Dec 2021 16:08
Last Modified: 06 Dec 2021 16:08
PMCID: PMC8603052

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