American Association for Cancer Research
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00085472can211017-sup-263310_4_supp_7448283_r0l4j1.xlsx (10.5 kB)

Supplementary Table S3 from A Combinatorial CRISPR–Cas9 Screen Identifies Ifenprodil as an Adjunct to Sorafenib for Liver Cancer Treatment

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posted on 2023-03-31, 04:45 authored by Feng Xu, Man Tong, Cindy S.W. Tong, Becky K.C. Chan, Hoi Yee Chu, Tin Lok Wong, John H.C. Fong, Maggie S.H. Cheung, Kylie Hin-Man Mak, Lakhansing Pardeshi, Yuanhua Huang, Koon Ho Wong, Gigi C.G. Choi, Stephanie Ma, Alan S.L. Wong

Supplementary Table S3

Funding

University of Hong Kong

Hong Kong Research Grants Council

Innovation and Technology Fund

Research Services and Knowledge Transfer Office

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ARTICLE ABSTRACT

Systematic testing of existing drugs and their combinations is an attractive strategy to exploit approved drugs for repurposing and identifying the best actionable treatment options. To expedite the search among many possible drug combinations, we designed a combinatorial CRISPR–Cas9 screen to inhibit druggable targets. Coblockade of the N-methyl-d-aspartate receptor (NMDAR) with targets of first-line kinase inhibitors reduced hepatocellular carcinoma (HCC) cell growth. Clinically, HCC patients with low NMDAR1 expression showed better survival. The clinically approved NMDAR antagonist ifenprodil synergized with sorafenib to induce the unfolded protein response, trigger cell-cycle arrest, downregulate genes associated with WNT signaling and stemness, and reduce self-renewal ability of HCC cells. In multiple HCC patient-derived organoids and human tumor xenograft models, the drug combination, but neither single drug alone, markedly reduced tumor-initiating cancer cell frequency. Because ifenprodil has an established safety history for its use as a vasodilator in humans, our findings support the repurposing of this drug as an adjunct for HCC treatment to improve clinical outcome and reduce tumor recurrence. These results also validate an approach for readily discovering actionable combinations for cancer therapy. Combinatorial CRISPR–Cas9 screening identifies actionable targets for HCC therapy, uncovering the potential of combining the clinically approved drugs ifenprodil and sorafenib as a new effective treatment regimen.

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