SLC7A11 is a superior determinant of APR-246 (Eprenetapopt) response than TP53 mutation status

Fujihara, K. M.; Corrales-Benitez, M.; Cabalag, C. S.; Zhang, B. Z.; Ko, H. S.; Liu, D. S.; Simpson, K. J.; Haupt, Y.; Haupt, S.; Phillips, W. A.; Clemons, N. J.

doi:10.1101/2020.11.29.398875

bioRxiv · 10.1101/2020.11.29.398875

SLC7A11 is a superior determinant of APR-246 (Eprenetapopt) response than TP53 mutation status

Fujihara, K. M.·Corrales-Benitez, M.·Cabalag, C. S.·Zhang, B. Z.·Ko, H. S.·Liu, D. S.·Simpson, K. J.·Haupt, Y.·Haupt, S.·Phillips, W. A.·Clemons, N. J.

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Abstract

PurposeAPR-246 (Eprenetapopt) is in clinical development with a focus on haematological malignancies and is marketed as a mutant-p53 reactivation therapy. Currently, the detection of at least one TP53 mutation is an inclusion criterion for patient selection into most clinical trials. Preliminary results from our phase Ib/II clinical trial investigating APR-246 combined with combination chemotherapy (cisplatin and 5-Fluorouracil) in metastatic oesophageal cancer, together with previous pre-clinical studies, indicate that TP53 mutation status alone may not be a sufficient biomarker for response to APR-246. This study aimed to identify a robust biomarker for response to APR-246. MethodsCorrelation analysis of the PRIMA-1 activity (lead compound to APR-246) with mutational status, gene expression, protein expression and metabolite abundance across over 800 cancer cell lines was performed. Functional validation and a boutique siRNA screen of over 750 redox-related genes were also conducted. ResultsTP53 mutation status was not predictive of response to APR-246. The expression of SLC7A11, the cystine/glutamate transporter, was identified as a superior determinant of response to APR-246. Genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53 and c-Myc were confirmed to also regulate cancer cell sensitivity to APR-246. ConclusionsSLC7A11 expression is the major determinant of sensitivity to APR-246 and should be utilised as a predictive biomarker in future clinical investigation of APR-246.

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Fujihara, K. M., Corrales-Benitez, M., Cabalag, C. S., Zhang, B. Z., Ko, H. S., Liu, D. S., Simpson, K. J., Haupt, Y., Haupt, S., Phillips, W. A., Clemons, N. J.. 2020-11-29. SLC7A11 is a superior determinant of APR-246 (Eprenetapopt) response than TP53 mutation status. https://doi.org/10.1101/2020.11.29.398875

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