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

iScience (2021-11-27)
Haider Inam, Ivan Sokirniy, Yiyun Rao, Anushka Shah, Farnaz Naeemikia, Edward O'Brien, Cheng Dong, David M McCandlish, Justin R Pritchard
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
Sigma-Aldrich
Phenylmethanesulfonyl fluoride, ≥98.5% (GC)
Sigma-Aldrich
Ponceau S solution, BioReagent, suitable for electrophoresis, 0.1 % (w/v) in 5% acetic acid