While A-1331852 was cytotoxic yet weakly immunogenic, its combination with OT-55 enhanced DAMP release, increased CD8⁺ effector functions, and, with PD-1/Tim-3 blockade, achieved local and distant tumor control with low toxicity. These findings identify OT-55 as an immunogenic adjuvant converting tolerogenic BH3 mimetic-driven apoptosis into ICD, providing a proof-of-concept immunogenic treatment for myelomonocytic AML.

In this study, in vivo testing of a large collection of patient-derived xenograft (PDX) models from melanoma patients with acquired resistance to BRAFi or BRAFi+MEKi shows that combining BCL2 inhibitors (BCL2i; navitoclax or venetoclax) with BRAFi+MEKi induces tumor regressions in a subset of these PDXs. Further, combining BRAFi+MEKi with an MCL1 inhibitor (MCL1i) counteracts resistance and interestingly decreases MCL1i-associated markers of cardiotoxicity. Together these studies identify potential personalized strategies to improve outcomes in this challenging patient population.

Lastly, enhanced in vivo antitumor activity of vobramitamab duocarmazine by systemic A-1331852 was shown. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with BCL-XL inhibitors for mCRPC.

The cytotoxic and antifibrotic effects of the BCL-XL inhibitor ABT-263 (navitoclax), alone or combined with the JAK2 inhibitor ruxolitinib, were evaluated in stromal and hematopoietic contexts. Combined inhibition of BCL-XL and JAK2 produced synergistic antifibrotic and pro-apoptotic effects in MSCs, post-MPN acute myeloid leukemia (AML) cell lines, and patient-derived cells resistant to ruxolitinib. Collectively, these findings identified BCL-XL as a key mediator of MPN-associated fibrosis and therapeutic resistance, and confirmed dual targeting of BCL-XL and JAK2 as a rational strategy for advanced MPN.

P2, N=32, Not yet recruiting, Peking University People's Hospital

Importantly, this synergistic interaction was tumor-specific and absent in non-malignant fibroblasts, indicating a favorable therapeutic window. Together, these findings highlight the mevalonate pathway as a targetable metabolic dependency in ES and demonstrate how physiologically grounded 3D models can uncover clinically actionable treatment strategies that remain hidden in traditional 2D systems.

Indeed, genetic inactivation of NOXA, which reinforces the pro-survival function of MCL-1 in cancer cells, only postpones death upon exposure to Taxol and BCL-xL antagonism with A1331852. Importantly, a comparative analysis of secretomes from NOXA-proficient and NOXA-deficient cancer cells treated with Taxol revealed variations in the production of inflammatory cytokines, including IL-1α, IL-1β, and IL-18. Thus, induction of apoptosis or a vacuole-associated and inflammatory cell death, in breast cancer cells by antimitotic treatment, relies on pore-forming protein GSDME expression but also on a fine balance within the BCL2 family network.

Lung mesenchymal stem cells (MSCs; platelet-derived growth factor receptor α+ CD31- CD45- CD326- cells) were isolated and differentiated into myofibroblasts by culturing them with 15% fetal bovine serum (FBS) for 6 d. In asthmatic lungs, α-SMA+ myofibroblasts showed increased Bcl-xL expression, which was unaffected by dexamethasone (DEX) treatment. However, co-treatment with the Bcl-xL inhibitor navitoclax significantly restored steroid sensitivity...These findings indicate that Bcl-xL-expressing myofibroblasts contribute to the development of glucocorticoid resistance in fibrotic lungs in severe asthma. Targeting Bcl-xL may provide a novel therapeutic strategy to restore steroid responsiveness in severe asthma.

Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers.

P1/2, N=52, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Sep 2026 --> May 2026

Significantly, YTHDC1-depleted senescent cells displayed enhanced sensitivity to the senolytic agent, ABT-263. Collectively, these findings uncover a previously unrecognized epitranscriptomic-telomerase axis that dictates senescence escape, establishing YTHDC1 as a central node linking RNA modification to telomere maintenance, cellular senescence, and tumor progression.

P1, N=26, Not yet recruiting, Wake Forest University Health Sciences