Uprety, D. | bioRxiv Science

bioRxiv2024

Selective loss of Y chromosomes in lung adenocarcinoma modulates the tumor immune environment through cancer/testis antigens

There is increasing recognition that the allosomes, X and Y, play an important role in health and disease beyond the determination of biological sex. A loss of the Y chromosome (LOY) occurs in most solid tumors in males and is often associated with worse survival, suggesting that LOY may give tumor cells a growth or survival advantage. We here use an expression-based continuous measure of LOY that allows us to investigate LOY in lung adenocarcinoma (LUAD) using both bulk and single-cell expression data. We find evidence suggesting that LOY affects the tumor immune environment by altering cancer/testis antigen expression and consequently facilitating tumor immune evasion, also reflected in inferred gene regulatory networks. In immunotherapy data, we further show that LOY and changes in expression of particular cancer/testis antigens are associated with response to pembrolizumab treatment and outcome. This computational study provides new insights into the mechanisms behind LOY in LUAD and a powerful biomarker for predicting immunotherapy response in LUAD tumors in males.

cancer biology↗

bioRxiv2022

Inhibitor of the nuclear transport protein XPO1 enhances the anticancer efficacy of KRAS G12C inhibitors in preclinical models of KRAS G12C mutant cancers

The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C mutated non-small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy may not respond and generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor-resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin1 (XPO1), as a single agent. KRAS G12C inhibitor MRTX1257 in combination with selinexor suppressed the proliferation of KRAS G12C mutant cancer cell lines MiaPaCa-2 and NCI-H2122 in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C mutant cancer cells. A combination of selinexor with KRAS G12C inhibitors potentiated the inhibition of KRAS expression in MiaPaCa-2 cells. NF-kB protein expression was also markedly reduced by selinexor and MRTX1257 combination. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models. SignificanceIn this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for cancer patients that do not respond or develop resistance to KRAS G12C inhibitor treatment.

cancer biology↗