Abstract 4410: Targeting MEIS2 in platinum resistant ovarian cancer

Abstract Introduction: Ovarian cancer has the highest mortality rate among gynecological cancers. Relapse of the disease accompanied by chemoresistance is common; however, the biological causes are still unclear. Although initial chemotherapy succeeds in debulking the burden of OC, it promotes emergence of cancer stem cells (CSCs), which are responsible for driving tumor relapse and developing chemo-resistant tumors in OC. Myeloid Ecotropic Insertion Site 2 (MEIS), is a homeobox transcription factor (TF), deregulated in various cancers, which plays critical roles in regulating stem cell identity and cell fate decision. Here, we examined the role of MEIS2 in regulating stemness features that promote chemoresistance of OC, and the impact of a MEIS2 blockade on OC initiation and progression. ​ Methods: Paired isogenic OC cell lines (OVCAR4/5 and COV362 platinum sensitive (Pt-S) and resistant (Pt-R)) were used. MEIS2 expression level in these cells were assessed by q-RT-PCR and Western Blotting. The effects of MEIS2 inhibition (by using a pharmacological inhibitor MEIS2i and biological knockdown (KD) on OC cell survival were assessed using colony formation and cell proliferation assays, and on stemness features by flow cytometry for analysis of ALDH+ cancer stem cell (CSC) population and measurement of stemness-related gene expression. ​MEIS2 direct binding targets in OC cells, were examined using ChIP-seq. The anti-tumor effects of MEIS2 inhibition on Pt-R OC cells were tested in vivo. Results: MEIS2 expression levels were increased in Pt-R vs. Pt-S OC cells at mRNA and protein levels. Treatment with MEIS2i (500nM-1μM) reduced the number of colonies in OC cells by at least 2-fold change (p<0.001); however, proliferation of cells was not diminished. Treatment with MEIS2i (250nM-1μM, 48 hours) decreased ALDH+ CSCs population by at least ∼2-fold (p<0.05), and inhibited the expression of stemness associated genes ALDH1A1, ALDH1A3, and Sox2 (p<0.05), compared to vehicle control. Knock down of MEIS2 decreased the CSC population from 29.4% to 14.3% (p<0.05) and inhibited stemness gene expression (p<0.05). ​MEIS2 knockdown inhibited tumor initiating capacity in vivo. OC xenografts derived from MEIS2 knockdown OVCAR5 cells were more responsive to carboplatin in vivo (p<0.05) compared with control xenografts. By integrating ChIP seq and RNA seq, we identified stemness-associated genes, ALDH1A2 and CD44 as direct MEIS2 targets contributing to maintaining stemness and chemo-resistance. Conclusions: Overexpression of MEIS2 contributes to stemness in OC. MEIS2 blockade inhibited stemness traits that contribute to chemotherapy resistance and tumor relapse. Our results put forward MEIS2 as a potential new target. Citation Format: Yinu Wang, Natalia Obrochta, Junzui Li, Daniela Matei. Targeting MEIS2 in platinum resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4410.