Combined HASPIN and mTOR inhibition is synergistic against KRAS-driven carcinomas

Chenyue Xu; Qiongmei Gao; Zhengming Wu; Weijuan Lou; Xiaoyan Li; Menghui Wang; Nianhong Wang; Qingquan Li

doi:10.1016/j.tranon.2022.101540

Combined HASPIN and mTOR inhibition is synergistic against KRAS-driven carcinomas

Transl Oncol. 2022 Dec:26:101540. doi: 10.1016/j.tranon.2022.101540. Epub 2022 Sep 14.

Authors

Chenyue Xu¹, Qiongmei Gao², Zhengming Wu³, Weijuan Lou⁴, Xiaoyan Li⁵, Menghui Wang⁶, Nianhong Wang⁷, Qingquan Li⁸

Affiliations

¹ Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
² Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center of Diabetes, Shanghai 200233, China.
³ Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
⁴ Department of Nephrology, Shanghai Fourth People's Hospital, School of Medcine, Tongji University, Shanghai 200434, China.
⁵ Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
⁶ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
⁷ Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: wnh@fudan.edu.cn.
⁸ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: 061101040@fudan.edu.cn.

Abstract

Background: Oncogenic mutations in the KRAS gene are very common in human cancers, resulting in cells with well-characterized selective advantages. For more than three decades, the development of effective therapeutics to inhibit KRAS-driven tumorigenesis has proved a formidable challenge and KRAS was considered 'undruggable'. Therefore, multi-targeted therapy may provide a reasonable strategy for the effective treatment of KRAS-driven cancers. Here, we assess the efficacy and mechanistic rationale for combining HASPIN and mTOR inhibition as a potential therapy for cancers carrying KRAS mutations.

Methods: We investigated the synergistic effect of a combination of mTOR and HASPIN inhibitors on cell viability, cell cycle, cell apoptosis, DNA damage, and mitotic catastrophe using a panel of human KRAS-mutant and wild-type tumor cell lines. Subsequently, the human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of the dual therapy.

Results: We demonstrated that the combination of mTOR and HASPIN inhibitors induced potent synergistic cytotoxic effects in KRAS-mutant cell lines and delayed the growth of human tumor xenograft. Mechanistically, we showed that inhibiting of mTOR potentiates HASPIN inhibition by preventing the phosphorylation of H3 histones, exacerbating mitotic catastrophe and DNA damage in tumor cell lines with KRAS mutations, and this effect is due in part to a reduction in VRK1.

Conclusions: These findings indicate that increased DNA damage and mitotic catastrophe are the basis for the effective synergistic effect observed with mTOR and HASPIN inhibition, and support the clinical evaluation of this dual therapy in patients with KRAS-mutant tumors.

Keywords: Cancer; HASPIN; KRAS; VRK1; mTOR.