Abstract Background: Cell death resistant cancer cells are challenging to treat with existing therapies and are major drivers of recurrence, morbidity, and mortality. Novel cell death-modulating drugs show promise for enhancing the therapeutic efficacy of first-line chemotherapeutic agents and may potentially improve patient outcomes. Both apoptosis and ferroptosis sensitivities are known to be modulated by changes in the redox environment from excessive oxidative stress, however, the mechanisms that determine cell commitment to each form of cell death are unclear. Therefore, to investigate how cell death outcomes might be adapted by changes to the cellular redox environment we used the mitochondrial antioxidant Mitoquinone (MitoQ) as a tool compound to dissect differences between apoptosis and ferroptosis outcomes in response to chemotherapeutic agents. Methods: Wild-type and BAX-/-BAK-/- HeLa (human cervical cancer) cells, as well as B16-F10 (metastatic murine melanoma) wild-type cells were treated with MitoQ (0.1-1 µM) alone or in combination with either an apoptosis-inducing cocktail of BH3 mimetics (1 µM ABT-263 + 1 µM S63845) or a ferroptosis-inducing cocktail (1 µM RSL3 + 1 µM Erastin2). Inhibitors of apoptosis (Q-VD-OPh) and ferroptosis (Ferrostatin-1) were used as controls to confirm the cell death modality. After 48 hours, cell viability and stage of cell death were assessed by flow cytometry using TMRE staining, CellEvent Green Caspase 3/7 Reporter, Annexin V, and DAPI to detect mitochondrial outer membrane permeabilization, caspase activation, phosphatidylserine externalization and plasma membrane permeabilization, respectively. Results: In wild-type cancer cell lines, increasing MitoQ concentrations (doses up to 0.3 μM) enhanced the induction of apoptosis in response to BH3 mimetics but suppressed ferroptosis induction in response to GPX4/System xc- inhibition. Across all three cell lines, treatment with high doses of single-agent MitoQ (1 µM and above) induced a significant increase in cell death, even in BAX/BAK-deficient cells. Conclusion: These findings suggest that modulation of mitochondrial oxidative stress via MitoQ modulates cancer cell death outcomes, promoting apoptosis while suppressing ferroptosis at low doses. Further work is needed to elucidate the molecular mechanisms underlying these effects and their implications for modulating cancer cell death modalities to improve cancer therapy outcomes. Citation Format: Christopher W. Clark, Xingping Qin, Cameron Fraser, Jessalyn Ubellacker, Kristopher A. Sarosiek. The mitochondrial antioxidant mitoquinone alters cancer cell death outcomes in response to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4662.

Cancer patients are increasingly exposed to cannabinoids, the bioactive molecules produced by the Cannabis sativa La. plant. This trend is being driven by several factors: expanding cannabis legalization, FDA approval of select cannabinoids for the treatment of seizures and cancer therapy–induced toxicities, and prior reports suggesting that cannabinoids may have direct anti-cancer effects. Despite the growing frequency of cannabinoid exposure during cancer treatment, it remains unknown whether cannabinoids influence tumor cell responses to standard anti-cancer therapies. Using multiple glioblastoma multiforme (GBM) cell line models, we found that treatment with a range of cannabinoids including CP-55,940 (a synthetic cannabinoid that mimics the effects of naturally occurring THC), cannabigerovarin (CBGV), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD) and cannabielsoin (CBE) generally does not affect GBM cell viability, except in a limited number of cases at doses of 20 μM or higher. Strikingly, we instead find that cannabinoid treatment suppresses therapy-induced GBM cell death, including the apoptosis induced by the GBM standard-of-care treatments temozolomide and ionizing radiation. This suppression of therapy-induced apoptosis was also evident in assays of clonal outgrowth following combination treatment. Mechanistically, cannabinoid exposure decreased apoptotic priming and increased expression of the pro-survival protein BCL-XL in U251-MG GBM cells. In addition, cannabinoid treatment shifted the response of U251-MG cells to cancer therapies away from apoptosis and toward G1 cell cycle arrest, in association with induction of p21. Finally, we observed higher rates of apoptosis in immortalized human neural progenitor cells (ReNcells) than in GBM cells at equivalent doses of CBD, suggesting that the relatively high cannabinoid doses required to induce GBM apoptosis may also be toxic to normal neural cells. Overall, these findings raise the possibility that cannabinoids could negatively affect tumor responses to chemotherapy and radiation, underscoring the need to carefully evaluate these effects in future clinical trials.

Apoptotic bodies (ApoBDs) are a type of extracellular vesicle (EV) generated during the final stages of apoptosis. These vesicles were traditionally regarded as apoptotic cellular waste. More recently, they have begun to be recognized as mediators of intercellular communication via the delivery of diverse factors, with emerging roles in various physiological processes including immune regulation, cancer progression, and tissue repair. However, the lack of standardized methods for isolating and characterizing ApoBDs has limited both their study and potential application. Here, we present simple, efficient, and reproducible protocols for ApoBD isolation, characterization, and application to downstream experimental approaches. This protocol includes a two-step differential centrifugation to isolate ApoBDs and flow cytometry-based characterization, as well as optional steps such as caspase inhibitor-based modulation of ApoBD release and fluorescent labeling of ApoBDs for their tracking. Furthermore, we provide methods to evaluate ApoBD uptake by recipient cells, enabling subsequent downstream functional studies. These approaches promote the reproducibility and standardization of ApoBD research, providing a foundation to deepen our understanding of their functional roles and advance future clinical applications.

Ovarian cancer stem cells (CSCs) can seed recurrent drug-resistant disease. Likewise, non-CSCs can acquire CSC phenotypic properties. How this process is orchestrated is of interest to inform how it might be prevented. We tested the hypothesis that ovarian CSC and/or drug-resistant tumor cells confer stem-like properties via extracellular vesicles (EVs). We focused our investigation on how EVs might mediate EZH2 signaling to promote a phenotypic change in drug-sensitive, non-CSCs. To accomplish this, we utilized paired PARP inhibitor-sensitive and - resistant ovarian cancer (OvCa) cell lines, EZH2 knockdown lines, and patient-derived organoids (PDOs) originating from recurrent high-grade serous OvCa. Small EVs isolated from drug-sensitive, CSC and/or drug-resistant enriched cultures, PARP inhibitor (olaparib) resistant lines, or drug-treated (olaparib or carboplatin) lines were cultured with treatment naïve or sensitive lines for defined time points. The impact of small EV exposure was determined by assessing cell number, metabolic activity, viability, sphere and colony-forming capacity, ALDH activity, DNA damage, and changes in associated signaling pathways. We found that EVs from CSC or drug-resistant enriched cell fractions communicate CSC-like phenotypes to the more sensitive tumor cells via EZH2 canonical and non-canonical signaling pathways, promoting stemness. We conclude that EV-mediated activation of EZH2 signaling represents a targetable mechanism contributing to stemness-associated drug resistance in OvCa. Graphical abstract:

Background/Aim: Gliomas are the most common primary brain tumors, yet the molecular circuits that drive their malignancy remain incompletely defined. Here, using an integrative, multi-dimensional approach, we aimed to pinpoint key molecular drivers having both functional and clinical relevance to disease progression and tumor aggressiveness in gliomas. Materials and Methods: Genome-wide CRISPR-Cas9 dependency screen across 70 glioma cell lines was paired with tumor aggressiveness-targeted transcriptomic differential expression and survival analyses to pinpoint critical drivers of disease progression in gliomas. Functional and gene set enrichments as well as protein-protein interaction network analyses were used to identify dominant pathways and key hub genes, followed by independent validation across external transcriptomic and proteomic datasets. Upstream regulator analyses and alternative splicing profiling were performed to nominate regulatory drivers and derive a small nuclear ribonucleoprotein D2 polypeptide (SNRPD2)-associated splicing signature. Results: Initial screening uncovered 222 essential genes (Chronos<-1) in gliomas, 87 of which were overexpressed in tumors displaying proliferative, epithelial-mesenchymal transition, glycolytic, hypoxic, and inflammatory signatures, and were associated with poor overall survival, consistent with aggressive disease biology. These genes converged on alternative splicing regulation, proteasome function, and cell cycle, with spliceosome core component, SNRPD2 emerging as the top hub gene. High SNRPD2 expression was associated with disease aggressiveness, tumor progression, and adverse clinical outcomes. MYC was identified as a putative transcriptional driver of SNRPD2. High SNRPD2 expression was also linked to differential (oncogenic) alternative splicing of multiple cancer-associated genes, correlating with disease aggressiveness and poor clinical outcomes. Conclusion: These data establish SNRPD2 and its associated alternatively spliced repertoire as a central adaptive node linked to disease aggressiveness in gliomas, highlighting it as a potential therapeutic target in glioma patients.

Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS-FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.

Platelets are short-lived anucleate cells essential for primary hemostasis and recognized for their functions in thrombosis, immunity, antimicrobial defense, neurodegeneration, as well as cancer growth and metastasis. Their brief lifespan in circulation is controlled by the removal of sialic acid residues from the platelet surface (desialylation) and also the mitochondrial apoptosis pathway, with high expression of the anti-apoptotic protein BCL-XL being required for platelet survival. This dependence on BCL-XL has prevented the clinical deployment of recently developed small molecule inhibitors of BCL-XL, which have promising activity in solid as well as liquid cancers but cause on-target thrombocytopenia. Here, we investigate the functional relationship between platelet desialylation and apoptosis to determine how cross-talk between these mechanisms may impact platelet lifespan. We find that platelets progressively lose sialic acid residues and become more primed for apoptosis while in circulation, resulting in aged platelets that are desialylated and highly prone to undergoing apoptosis. In addition, platelet desialylation via endogenous or exogenous factors directly increases their BCL-XL dependence and accelerates apoptosis, which can be reversed by treatment with the sialidase inhibitor DANA (2,3-dehydro-2-deoxy-N-acetylneuraminic acid). Notably, young platelets recently released into circulation are less primed for apoptosis and less dependent on BCL-XL for survival. Consistent with these changes in priming, platelets aged in vitro exhibit increasing expression of multiple pro-apoptotic proteins including BIM, BAK and PUMA along with increasing cleaved caspase 3. Leveraging the lower BCL-XL dependence of young platelets, stimulation of de novo platelet production with the thrombopoietin receptor agonist romiplostim prevents BH3 mimetic-induced thrombocytopenia in vivo and may prevent severe platelet loss in patients treated with BCL-XL inhibitors.

The rarity of thymic epithelial tumors and absence of targetable alterations present significant challenges for identifying improved systemic therapies. Recent advances in single-cell sequencing have enhanced our understanding of normal thymus development and the factors underlying malignant transformation. During medullary epithelial differentiation in adulthood, anti-apoptotic factors are expressed, potentially increasing resistance to cell death and thus facilitating tumorigenic processes. We hypothesized that this resistance to apoptotic cell death might be a hallmark of thymic epithelial tumorigenesis and could generate therapeutic vulnerabilities. To investigate this possibility, we measured apoptotic priming and dependencies on anti-apoptotic proteins in metastatic, surgically-resected thymic epithelial tumors. We utilize dynamic BH3 profiling, a functional assay that detects induction of apoptosis in response to titrated doses of pro-apoptotic signals in viable cancer cells freshly isolated from resection specimens. Our interim results show that advanced, WHO B-subtype thymomas are highly primed for apoptotic cell death, even in chemotherapy-resistant tumors, supporting the notion that thymomas may be more radiosensitive than chemosensitive. Furthermore, we find that thymomas consistently exhibit dependence on anti-apoptotic proteins, which may be targeted by recently-developed BH3 mimetics that inhibit these proteins. Apoptotic priming and dependencies are further enhanced by co-treated with clinically-relevant, targeted anti-cancer agents. To understand the basis for these findings, we evaluate the role of apoptotic priming during normal thymic epithelial development to determine how apoptotic resistance aligns with other molecular features of medullary epithelial biology, including the transcription of non-thymic tissue antigens and DNA damage response. These findings have significant therapeutic implications for further clinical investigation and deepen the foundational knowledge of molecular factors contributing to tumorigenesis, revealing new opportunities for preclinical modeling. Citation Format: Christopher Nabel, Yin P. Hung, Brian Do, Xingping Qin, Cameron Fraser, Yolonda Colson, Michael Lanuti, Uma Sachdeva, Cameron Wright, Kris Sarosiek. Assessment of apoptotic priming in thymic epithelial tumors to define hallmarks of pathogenesis and novel therapeutic strategies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B015.

Bispecific T-cell Engagers (BITEs) are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors (ICI) by targeting a preidentified tumor associated antigen and redirecting a polyclonal population of effector T-cells against the tumor. High grade serous ovarian cancer is a lethal disease in the recurrent setting and has not been amenable to ICI therapy. MUC16/CA125 is overexpressed in high grade serous ovarian cancer. BITEs targeting the tumor-retained portion of MUC16/CA125 have recently been described and are in early-phase clinical trials. To identify mechanisms of resistance to BITEs, we collected serum, peripheral blood mononuclear cells, and ascites samples from patients with disease progression on MUC16-directed bispecific antibodies. Analysis of these samples showed downregulation of MUC16/CA125, elevated secretion of VEGF, and epithelial-to-mesenchymal transition in tumor cells. Interestingly, hypoxia was determined to be a driver of these changes. These findings were prospectively validated in ovarian cancer cell lines with CRISPR/Cas9 knockout of MUC16/CA125 and VEGF. Peripheral blood mononuclear cells from patients with disease progression were capable of effective cytolysis ex vivo, suggesting that resistance to therapy was primarily tumor driven. Restoration of MUC16/CA125 expression did not restore cytotoxicity in the presence of increased VEGF secretion. Combination treatment with a VEGF inhibitor rescued cytotoxicity in hypoxia-conditioned ovarian cancer cell lines with preserved target antigen expression. Collectively, these data outline a link between hypoxia and the development of resistance to BITEs and posits inhibition of VEGF inhibition as a potentially important therapeutic intervention.

Paclitaxel and other microtubule-targeting agents are cornerstone therapies for diverse cancers, including lung, breast, cervical, pancreatic, and ovarian malignancies. Paclitaxel induces tumor cell apoptosis during mitosis by disrupting microtubule dynamics required for chromosome segregation. However, despite initial responsiveness, many tumors develop resistance, limiting therapeutic durability. Here, we used high-grade serous ovarian carcinoma (HGSOC), the most common and lethal subtype of ovarian cancer, as a model to dissect the mechanisms underlying this resistance. We find that paclitaxel-induced mitotic arrest triggers degradation of the pro-survival protein MCL-1 and upregulation of BCL-XL, followed by inactivating phosphorylation of BCL-XL at Ser62 to promote apoptosis. In resistant cells, this MCL-1 downregulation is insufficient to commit cells to apoptosis but instead results in a transient convergence of apoptotic dependencies by forcing BCL-XL to sequester the pro-apoptotic proteins BIM, BAX, and BAK. During this state, BCL-XL inhibition induces synergistic apoptosis, even in chemoresistant cells. Surprisingly, we also discover that loss of substrate attachment recapitulates this apoptotic convergence both in vitro and in vivo, with HGSOC cells growing in metastasis-promoting malignant ascites displaying heightened apoptotic priming and dependence on BCL-XL relative to solid tumors. In HGSOC xenografts, targeted degradation of BCL-XL using the platelet-sparing proteolysis-targeting chimera (PROTAC) DT2216 matches the efficacy of paclitaxel monotherapy while avoiding the chronic thrombocytopenia induced by BCL-XL inhibitors such as navitoclax (ABT-263). Strikingly, combination therapy leveraging the synergy between paclitaxel and DT2216 leads to complete eradication of HGSOC cell line and patient-derived xenografts. Moreover, DT2216 treatment blunts the rapid apoptotic adaptation caused by other BCL-XL inhibitors, indicating that targeted degradation of pro-survival proteins may yield more durable responses than inhibition alone. These findings uncover a mechanistic framework for safely exploiting the apoptotic dependency convergence caused by mitotic arrest and substrate detachment and support the clinical development of BCL-XL-targeting PROTACs to overcome chemoresistance in ovarian cancer and other solid tumors.

The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.

Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.

Ovarian clear cell carcinoma (OCCC) is a rare subtype of ovarian cancer with resistance to chemotherapy and poor prognosis in advanced-stage disease. OCCC has frequent alterations in the SWI/SNF chromatin remodeling complex and dysregulation of the PI3K and MAPK and HIF/VEGF signaling pathways. We showed that many OCCC cell lines are sensitive to inhibition of BCL-XL, a pro-survival protein in the intrinsic pathway of apoptosis. A BCL-XL inhibitor (A1331852) or a PROTAC degrader of BCL-XL (DT2216) promoted cell death in OCCC cell lines in combination with cisplatin or paclitaxel. Using Annexin V/PI staining and BH3 profiling (a functional assay for apoptotic priming) we found that BCL-XL inhibition or degradation combined with paclitaxel increased apoptotic cell death beyond the effect of either agent alone. We are currently analyzing reverse phase protein array data to identify upregulated and downregulated proteins in OCCC cells treated with A1331852, paclitaxel, or both. The combination of DT2216 and weekly paclitaxel is being evaluated in a phase 1b clinical trial in recurrent platinum-resistant ovarian cancer (NCT06964009, Dialectic Therapeutics). In addition, we performed chemical screens in OCCC cell lines (OVISE, OVTOKO, JHOC5, TOV21G) to identify compounds that can promote apoptotic cell death in OCCC as single agents and/or combined with BCL-XL inhibition. We applied a Selleck bioactive compound library (1,902 compounds, emphasizing FDA-approved agents) either alone or combined with BCL-XL inhibitor A1331852 at a fixed concentration (IC25 for each cell line). We used a microscopy-based assay to quantitate surviving cells after 72 hours of treatment. We focused on the set of compounds with enhanced activity when combined with A1331852 compared to monotherapy. We performed a 6-dose validation experiment with 53 compounds predicted to synergize with A1331852, from which we selected ten compounds with strong activity combined with A1331852 and validated their activity in 9 OCCC cell lines. We selected three compounds showing consistent synergy with A1331852 for further investigation: RAF265 (RAF/VEGFR inhibitor), PTC209 (BMI1 inhibitor), and PIK-75 (PI3K alpha inhibitor with other targets including CDK9 and DNA-PK). All three compounds induce cell death in multiple OCCC cell lines, which is enhanced by BCL-XL inhibition. Annexin V/PI flow cytometry demonstrated induction of apoptosis with single agent and A1331852 combination treatment. BH3 profiling in OCCC cell lines revealed that treatment with each of the novel agents promoted apoptotic priming, and this was further increased by combined treatment with A1331852. We are analyzing changes in apoptotic proteins and drug target proteins to identify potential mechanisms of synergy of the combinations. In summary, targeting BCL-XL by small molecule inhibitors or PROTAC degrader DT2216 may promote apoptotic cell death in OCCC in combination with paclitaxel chemotherapy or targeted agents. Brendan Shay, Abram Handly-Santana, Jaeyoung Kang, Lissah Johnson, Xingping Qin, Daohong Zhou, Stover Elizabeth. Combination strategies with BCL-XL inhibition or degradation in ovarian clear cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A026.

BCL-XL is a pro-survival protein that restrains pro-apoptotic proteins and protects cells from apoptotic cell death. BCL-XL inhibition promotes cell death in ovarian cancer cells treated with chemotherapy. Clinical use of BCL-XL inhibitors has been limited by thrombocytopenia due to platelet dependency on BCL-XL. DT2216 is a proteolysis targeting chimera (PROTAC) degrader of BCL-XL, comprised of a VHL E3 ubiquitin ligase ligand and an ABT-263 moiety based BCL-XL binder that targets BCL-XL to VHL for ubiquitination and proteasomal degradation. Because VHL expression is low in platelets, DT2216 causes less thrombocytopenia than BCL-XL inhibitors. A phase I safety and tolerability trial in 20 patients with solid tumors (Dialectic Therapeutics) established a recommended DT2216 dose of 0.4 mg/kg intravenously (IV) twice weekly and showed BCL-XL degradation in peripheral white blood cells. Single-agent DT2216 was well tolerated; the most common toxicity was thrombocytopenia that was typically transient and did not require cessation of DT2216. In pre-clinical models, DT2216 combined with paclitaxel showed significant growth inhibition and apoptosis induction in high-grade serous ovarian cancer in vitro and in vivo. This is a phase 1b study of twice weekly DT2216 combined with weekly paclitaxel in platinum-resistant ovarian cancer (clinicaltrials.gov NCT06964009). It is a dose-escalation study with a BOIN design and a dose level 0 of 0.32 mg/kg DT2216 (DT) IV twice weekly and 70 mg/m2 paclitaxel (Pac) IV weekly, with possible escalation to a maximum of 0.4 mg/kg DT and 80 mg/m2 Pac or de-escalation to 0.24 or 0.2 mg/kg DT and 70 mg/m2 Pac. Participants will be treated with DT2216 IV twice weekly (D1,4,8,11,15,22,25) and paclitaxel IV weekly (D1,8,15) in a 28-day cycle. Key inclusion criteria include a diagnosis of relapsed or refractory platinum-resistant epithelial ovarian cancer and four or fewer lines of prior systemic therapy. Key exclusion criteria include prior weekly paclitaxel in the recurrent setting or prior treatment with a BCL-XL inhibitor, and complications including recent surgery or bowel obstruction, clinically significant ascites or pleural effusion, and dependency upon parenteral nutrition or IV fluids. The primary endpoint is to determine the maximum tolerated dose and the recommended phase 2 dose of the combination of twice weekly DT2216 plus weekly paclitaxel. Secondary endpoints include evaluating the safety of DT2216 combined with paclitaxel based on the frequency and type of adverse events during treatment, and assessing the efficacy of DT2216 combined with paclitaxel based on overall response rate, median progression-free survival and duration of response. Translational objectives include measuring the pharmacokinetics of DT2216 and paclitaxel when given in combination; quantitating BCL-XL levels in peripheral white blood cells to measure DT2216-mediated degradation of BCL-XL; and evaluating candidate biomarkers of response to DT2216 plus paclitaxel. Approximately 30 patients are expected to enroll. Elizabeth H. Stover, Xingping Qin, Martin Hayes, Caroline Barabell, Su-Chun Cheng, Brendan Shay, Oyku E. Sumer, Atomu Yamaguchi, Stacy N. Suberg, Joshua Sills, Larry Tremaine, Robert Hromas, James Strauss, Michael Kurman, Joan S. Brugge, Meghan E. Shea, Daohong Zhou, Kristopher A. Sarosiek, Nabihah Tayob, Ursula A. Matulonis, Joyce F. Liu. Phase 1b trial of BCL-XL degrader DT2216 and weekly paclitaxel in recurrent platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B004.