Exploring eIF1AX as a specific vulnerability in loss of chromosome Y (LOY) tumors

Certain types of cancer differentially affect females and males. Recent studies implicated the loss of chromosome Y (LOY) as one of the mechanisms driving male-specific cancers. In these tumors, the loss of paralog Y-linked genes such as eIF1AY creates a dependency on the remaining X-linked eIF1AX paralog gene, which encodes the essential translation initiation factor eIF1A. Likewise, certain female cancers are highly vulnerable to eIF1AX depletion due to the a priori limiting amounts of eIF1A. Thus, targeting eIF1AX presents a potentially precise therapeutic strategy for LOY male tumors or certain female cancers. Additionally, eIF1AX is the only example of a translation initiation factor that is recurrently mutated in cancer. We have previously elucidated the function of eIF1A and its cancer-associated mutants and most recently identified the first eIF1A-specific small molecule inhibitors called 1Ais. In this project, we proposed examining the idea that eIF1AX inhibition by 1Ais is a potentially novel, personalized therapeutic approach against female and male-specific cancers that display rate-limiting amounts of eIF1A. We are currently using CRISPR-Cas9 to mutate the chrY-encoded eIF1AY in the male cancer cell line HCT116 to determine how the loss of eIF1AY influences sensitivity to 1Ais. Likewise, we plan to reduce eIF1AX levels in ovarian cancer cell lines by siRNA or CRISPR-Cas9 to assess the sensitivity to 1Ais. Once these experiments are complete, we will evaluate 1Ais in preclinical xenograft models with LOY. We will also soon start to determine the synergistic effects of 1Ais with DNA-damaging chemotherapies. We anticipate that this study will validate eIF1A as a druggable target in specific types of cancer.