Abstract PO-001: HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation

Abstract

Triple-negative breast cancer (TNBC) accounts for 15% ~ 20% of overall breast cancer cases and exhibits earlier age of onset, high metastasis, and aggressiveness with poor clinical outcomes shown by higher relapse and lower survival rates than other types of breast cancer. TNBC contributes to the major mortality of breast cancer patients. Treatments of TNBC patients are still limited to surgery, chemotherapy, or radiation since the absence of cell receptors makes targeted hormonal therapies impossible. Targeting cysteine-dependence is an emergent strategy to treat the mesenchymal TNBC. However, many TNBC cells are non-mesenchymal and irresponsive to cysteine deprivation. To overcome such resistances, three selective HDAC6 inhibitors (Tubacin, CAY10603, and Tubastatin A), identified by epigenetic compound library screening, can synergize with cysteine deprivation to induce cell death in the non-mesenchymal TNBC. Despite the efficacy of the HDAC6 inhibitor, knockout of HDAC6 did not mimic the synthetic lethality induced by its inhibitors, particularly tubacin, indicating that HDAC6 is not the actual target of HDAC6 inhibitor in this context. Instead, transcriptomic profiling showed that tubacin triggers an extensive gene transcriptional program in combination with erastin, a cysteine transport blocker. Notably, the zinc-related gene response and an increase of labile zinc were induced in cells by the combination treatment. We found that the disturbance of cellular zinc homeostasis was driven by PKCγ activation, which revealed that the PKCγ signaling pathway is required for HDAC6 inhibitor-mediated synthetic lethality. Overall, our study identifies a novel function of HDAC6 inhibitors that function as potent sensitizers of cysteine deprivation. HDAC6 inhibitors are capable to overcome cysteine independence in non-mesenchymal tumor cells, which allows the application of targeted cysteine-dependence therapy in various subtypes of breast cancer. Citation Format: Tahiyat Alothaim, Morgan Charbonneau, Xiaohu (Mark) Tang. HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-001.