Abstract CKAP2 regulates microtubule dynamics and organization in cells. Bioinformatic analysis in the TCGA and OncoSG cohorts revealed that CKAP2 is one of the top upregulated genes associated with poor overall survival in Lung Adenocarcinoma (LUAD) patients. IHC analysis on LUAD-TMA confirmed that CKAP2 was significantly upregulated compared with normal, and elevated CKAP2 levels was associated with poor overall survival. In LUAD cells, CKAP2 targeting siRNA reduced viability, induced cell-death, hindered invasion, impaired colony and spheroid formation efficiency, and lowered the PI3K pathway activity. Mechanistically, miR-497-3p effectively suppressed the transcript and protein expression of CKAP2 through binding to CKAP2 mRNA 3’-UTR. Ectopic expression of miR-497-3p mimicking the effects of siRNA-mediated knockdown of CKAP2. Transcriptomic analysis revealed that CKAP2 knockdown inhibits activity of NRF2 and its downstream targets expression. This was accompanied with the suppression of autophagy, anti-oxidant, and cytoprotective genes in LUAD cells, causing increased sensitivity towards various cytotoxic and oxidative agents, as well as enhanced lipid peroxidation. Lastly, circo-plot analysis indicating LRRK2 as a potential candidate promotes oxidative stress sensitization. To further explore CKAP2 as a therapeutic target, HTVS identified the small molecule BFH772 as a novel CKAP2 inhibitor. CETSA validated the binding between BFH772 and CKAP2. BFH772 preferentially inhibited CKAP2-high lung adenocarcinoma cells as a monotherapy or in combination with platinum chemotherapy, in vitro and in vivo. However, the safety profile of BFH772 had not been assessed clinically. Electrophysiological characterization followd by AI-modeling suggested BFH772 may carry risks of adverse effects such as dermatitis, diarrhea, and anaphylaxis. Proper safety measures are advised during clinical development to closely monitor for these potential issues and implement strategies to mitigate risks to study participants. These findings suggest that CKAP2 is an important prognostic marker of NSCLC cells, and co-targeting CKAP2 could sensitize these cells to existing therapies such as cisplatin/ carboplatin. Citation Format: SF Yeung, Mingo MH Yung, Cherie TY Law, Julia YH Liu, Kim Li, July Chen Xi, Alex Law CH, Mandy Chan CM, Mary P. Chiu, Cathy Fung Sin Hang, Stephen Liang Yongho, Helen Chan HY, Stephen Tsui KW. Targeting CKAP2 as a Therapeutic Strategy to Enhance Sensitivity of Lung Adenocarcinoma to Chemotherapy abstract. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P15.
Yeung et al. (Fri,) studied this question.
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