A-1331852 / AbbVie - LARVOL DELTA

Synergy between enzalutamide and selective Bcl-2 family inhibitors in metastatic castration-resistant prostate cancer (ESMO Asia 2025) - "While venetoclax (Bcl-2 inhibitor) combinations with enzalutamide have entered clinical evaluation, the relative benefit of inhibiting different Bcl-2 family members under identical experimental conditions has not been directly compared. DU145 mCRPC cells were treated for 48 h with enzalutamide (ENZA) alone or in combination with ABT-199 (Bcl-2 inhibitor), A-1331852 (Bcl-xL inhibitor), or AZD5991 (Mcl-1 inhibitor). In a direct comparison under uniform conditions, Mcl-1 inhibition with AZD5991 emerged as the most effective partner for ENZA in DU145 cells, followed by Bcl-xL inhibition, while Bcl-2 inhibition was less impactful. These findings support further evaluation of Mcl-1-targeting strategies as a means to overcome AR-independent resistance in mCRPC, while underscoring the need for cautious interpretation of large in-vitro dose-reduction estimates."

IO biomarker • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • BCL2L1

SRSF2 mutation induces BH3 mimetics sensitivity via BCL2L2 mis-splicing (ASH 2025) - "Interestingly, SRSF2 mutation conferred increased sensitivity tothe MCL1 inhibitor (S-63845) or the BCL2L1 inhibitor (A-1331852) in AML cell lines that were otherwiseinsensitive to venetoclax, in a manner dependent on their intrinsic BH3 family protein expression profile.These findings suggest that SRSF2 mutations induce a shift in apoptotic dependency, with variableconsequences shaped by the intrinsic anti-apoptotic landscape of the cell.To uncover the molecular basis of this shift, we analyzed the expression of BCL2 family members inSRSF2-mutant and wild-type cells. Our results uncover amechanistically defined and therapeutically actionable vulnerability in SRSF2-mutant AML and providebroader insight into how splicing factor mutations reshape apoptotic regulation in leukemia. Thesefindings may inform the rational design of combination therapies and support the development ofprecision medicine strategies targeting splicing-derived vulnerabilities in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2L1 • BCL2L2 • GLI2 • SRSF2

Inhibition of PRMT5 with JNJ-64619178 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptosis (ASH 2025) - P1 | "Various cell lines, including DLBCL (TMD8, Ri-1, OCI-Ly1,OCI-Ly1R, SUDHL4), double-hit lymphoma patient-derived xenograft (DW19), MCL (Mino, Jeko-1), and BL(Raji, BL-70) were utilized to investigate the in vitro anti-cancer properties of JNJ-9178, BH3 mimetics(venetoclax [Ven, BCL-2i], S63845 [S63, MCL-1i], A1331852 [A133, BCL-xLi]) and TRAIL analogs (rhTRAIL[recombinant human TRAIL], Conatumumab [DR5 agonist], and Mapatumumab [DR4 agonist]). We identified PRMT5 as an important regulator of both intrinsic and extrinsic apoptosis. Ourdata suggest that DBP has the potential to optimize the selection of BH3 mimetics to combine with JNJ-9178 to maximize the activity of this drug across certain B-cell NHL subtypes. Additionally, JNJ-9178sensitizes B-cell NHL cell lines to TRAIL-induced cancer cell-selective extrinsic apoptosis."

IO biomarker • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Solid Tumor • ANXA5 • BCL2 • TNFRSF10B

Integrative Analysis of Transcriptomic and Proteomic Data Identifies Patterns of Primary Resistance to Venetoclax-Azacitidine and Reveals Targetable Vulnerabilities in Acute Myeloid Leukemia (AML) (ASH 2024) - "Results : In the BCL2 family inhibitor drug sensitivity assay, navitoclax (BCL2/BCLXLi) was the most effective in killing AML blasts of VEN-AZA refractory patients (mean IC50 70 nM) compared with venetoclax (BCL-2i) (1000 nM), A-1331852 (BCLXLi) (1000 nM) and S-63845 (MCL1i) (> 1000 nM)...Patients with high overall TNF expression (C1) were selectively responsive to the IAP inhibitors birinapant and LCL161 ex vivo, suggesting that inhibition of IAPs could be an effective approach for VEN-AZA resistant AML with increased TNF...Additionally, a MEP-like gene signature, combined with eleveted TNF expression in AML blasts, may contribute to venetoclax resistance while concurrently enhancing sensitivity to SMAC mimetics. These findings suggest potential therapeutic targets and stratification markers, paving the way for novel therapy approaches for VEN-AZA refractory AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CD276 • CD34 • KIT • MCL1 • MECOM • PRAME • TP53

BCL-Xl Represents a Novel Therapeutic Target in Type 2 Mutant Calr-Driven Myeloproliferative Neoplasms (ASH 2023) - "In cells treated with JAK inhibitor ruxolitinib, we found that while BCL-xL expression levels decreased nearly 90% in ruxolitinib treated CALRdel52 cells, this decrease was much more modest in CALRins5 cells, suggesting JAK/STAT activation is only partially responsible for BCL-xL up-regulation in CALRins5 MPN cells. We observed that CALRins5 cells displayed decreased viability in response to A-1331852 alone and in combination treatments, suggesting an increased sensitivity to BCL-xL inhibition. In conclusion, we demonstrate that CALRins5-driven MPN cells display an enhanced sensitivity to BCL-xL inhibition, which may represent an effective therapeutic approach for CALRins5+ MPN patients."

IO biomarker • Essential Thrombocythemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytosis • ATF6 • BCL2 • BCL2L1 • CALR • HSP90AA1

Protein Degrader WH25244 Eliminates Venetoclax Resistance Factors: Mutant or Hyperphosphorylated BCL2, and BCL-XL (ASH 2024) - "WH25244 is a bifunctional molecule derived from navitoclax that recruits VHL E3 ligases to BCL2 and BCL-XL proteins, resulting in degradation via the ubiquitin-proteasome system...As assessed by CellTiter-Glo at 24h, WH25244 was potent against four cell lines sensitive to the BCL-XL inhibitor A-1331852 (EC50s 5000 nM) : MOLT-4 (EC50 = 4 nM), PF-382 (EC50 = 20 nM), SUP-T11 (EC50 = 30 nM), and CCRF-CEM (EC50 = 350 nM)...In conclusion, our results indicate that WH25244 can degrade mutant BCL2, hyperphosphorylated BCL2, and BCL-XL, overcoming multiple mechanisms that drive resistance to venetoclax. These data justify continued preclinical and future clinical investigation of WH25244 in CLL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ANXA5 • BCL2 • BCL2L1 • MCL1 • NCAM1

FRET two-hybrid assay-based target drug screening in living cells. (PubMed, J Biotechnol) - "The FRET-HBTDS method was performed on the FRETscope with a 20× objective for the cells co-expressing CFP-Bcl-xL and YFP-Bak to assess the action of eight compounds (A1331852, S63845, AC, DSF/Cu, Met, REGO, SOFA, ABT199) on the interaction between Bcl-xL and Bak. Our data firmly demonstrate that A1331852 unlocks the binding state of Bcl-xL and Bak, while DSF/Cu modifies the structure of the Bcl-xL-Bak complex. These findings demonstrate that FRET-HBTDS can be used to assess the efficacy of a drug by revealing the binding state and complex molecular structure of the target proteins using FRET technology in living cells, which may be a potential targeted drug screening method."

Journal • Oncology • BCL2L1 • CFP

Identification of vulnerabilities for targeting BCL-2 family members in T-Cell Acute Lymphoblastic Leukemia (ASH 2023) - "Venetoclax is a selective BCL-2 inhibitor and is successfully used in CLL and AML, but heterogeneous sensitivity to venetoclax has been described in ALL and inhibitors of other BCL-2 family members including BCL-XL-selective A-1331852 and MCL-1 selective AZD5991 have been developed. Moreover, a dual inhibitor of the anti-apoptotic BCL-2 family members BCL-2 and BCL-XL (AZD4320) with its dendrimer conjugate (AZD0466) has recently shown anti-tumor activity in hematologic cancer models with manageable toxicity...Taken together, we found vulnerabilities of T-ALL to BCL-2 family inhibition, particularly to dual BCL-2/BCL-XL inhibition by AZD4320, and we demonstrated on-target activities. Using BH3-profiling, we identified BAD-priming as a marker of response for AZD4320 and MCL-1 dependence as a resistance mechanism that can be targeted by combination treatment, suggesting further clinical evaluation."

IO biomarker • Acute Lymphocytic Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • BCL2 • BCL2L1

Inhibition of Cyclin-Dependent Kinase 9 Rapidly Induces Apoptosis in Acute Lymphoblastic Leukemia and Shows Synergistic Activity with BH3-Mimetics (ASH 2024) - "Using the multi-CDK inhibitor dinaciclib, which targets CDK1, 2, 5 and 9, and the specific CDK9 inhibitor AZD4573, we analyzed the effects of both inhibitors in a series of ALL cell lines (BCP-ALL n=10, T-ALL n=6) and primary, patient-derived xenograft (PDX) samples (BCP-ALL n=15, T-ALL n=9)...Based on this, we investigated combinatorial inhibition of CDK9 (AZD4573) together with inhibitors of BCL-2 or BCL-XL (venetoclax, A-1331852, AZD4320) using dose-response matrix analyses and found enhanced cell death and synergistic activity for both combinations...However, intrinsic insensitivity due to dysbalanced protein levels of pro-survival proteins might limit efficacy. Combining CDK9 inhibition with inhibitors of the anti-apoptotic molecules BCL-2/BCL-XL significantly enhances cell death, thus overcoming insensitivity and providing an effective, novel therapeutic anti-ALL strategy to be further evaluated for clinical application."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ANXA5 • BCL2L1 • CASP3 • CDK1 • CDK9 • MCL1

Acquired Venetoclax Resistance in an In Vivo Model of B-Cell Precursor Acute Lymphoblastic Leukemia Is Characterized By Altered Functions of Apoptosis Regulators (ASH 2023) - "This shift was also reflected in an ex vivo drug treatment assay showing decreased sensitivity to the MCL-1 inhibitor S63845 and the BCL-XL inhibitor A-1331852 in ALL cells from VEN- treated mice compared to control- treated mice (S63845 EC50 1.5 vs. 2.2 µM, A-1331852 EC50 9.3 vs. 15.3 µM). Taken together, acquired VEN-resistance was recapitulated in a co-clinical trial model of BCP-ALL with repeated in vivo treatment cycles showing lower drug sensitivities along with increasingly reduced in vivo anti-ALL activity of VEN. Characterization of acquired VEN-resistance revealed decreased functional dependency on anti-apoptotic proteins and downregulation of pro-apoptotic BIM and BAX, thus pointing to an imbalance of pro- and anti-apoptotic molecules, which can be potentially targeted by directed compounds bypassing resistance to specific BCL-2 inhibition."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • KMT2A

Mechanistic Insights and Therapeutic Potential of a PRMT5 Inhibitor Combined with Venetoclax in B Cell Malignancies (ASH 2024) - P1, P1/2 | "DLBCL (TMD8, RI-1, OCI-Ly1, SUDHL4), double-hit lymphoma (DHL) patient-derived xenograft (PDX) cell line (DW19), MCL (Mino, Jeko-1), and Burkitt lymphoma (Raji) cell lines were utilized to investigate the in vitro anti-cancer properties of P1 and BH3 mimetics (venetoclax [BCL2i], S63845 [S63, MCL-1i], A1331852 [A133, BCL-xLi], Selleckchem). The caspase 8 inhibitor Z-IETD-FMK also rescued drug-induced cell death, but not as much as Z-VAD-FMK, suggesting potential activation of the extrinsic apoptosis pathway by the combined use of P1 and venetoclax. Conclusions : Our study suggests that the combination of a PRMT5 inhibitor P1 with venetoclax potently induces both intrinsic and extrinsic apoptotic cell death and may serve as a potential therapeutic strategy to explore further for DLBCL and MCL."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ANXA5 • CASP8

Combining BCL-XL Inhibition with Brentuximab Vedotin to Overcome Chemoresistance in EBV-Related T/NK Lymphoma (ASH 2023) - "MethodsA diverse panel of EBV+ T/NK lymphoma cell lines including SNK1, MECO4, SNK6, SNT8, SNK10, SNT15 and SNT16 were evaluated for sensitivity to MMAE alone and with specific BH3 family inhibitors including A1331852, inhibiting BCL-XL, venetoclax inhibiting and BCL-2 and the MCL-1 inhibitor S63845 (Generon). These data show the potential of BV with BCL-XL inhibition to be an effective and tolerable treatment for ENKTL. We are now planning a detailed preclinical study to better understand the efficacy and safety of this combination in vivo and progress towards a future clinical trial."

IO biomarker • Epstein-Barr Virus Infections • Extranodal Natural Killer/T-cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Natural Killer/T-cell Lymphoma • Oncology • Thrombocytopenia • BCL2 • BCL2L1 • TNFRSF8

Evaluation of the efficacy of novel ADCs as potential therapy options for colorectal cancer using a patient derived organoid model (DGHO 2025) - "This study investigates novel ADCs targeting B7-H3 (mirzotamab clezutoclax, ABBV-155) and EGFR (ABBV-637) linked to a Bcl-xL inhibitor as payload as therapeutic strategies for colorectal cancer using a PDO system. Four selected PDOs from CRC patients were maintained in long-term culture...Additionally, an internalization assay utilizing a pH-sensitive fluorescent dye (pHAb) was performed to assess drug uptake and intracellular localization of the ADCs. Untargeted inhibition of Bcl-xL with small molecule inhibitor A-1331852 caused significant cell viability loss (max reduction: 97% at 10 µM) and organoid structural disintegration, with efficacy correlating with baseline protein expression (r = 0.92)...Combinatorial targeting (ABBV-155 + Mcl-1 inhibitor ABBV-467) synergistically enhanced cell death (viability reduction: 62.6% vs. 0% monotherapy). These data provide critical insights into the use of novel ADCs as therapeutic options for CRC patients and suggest that..."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • BCL2L1 • EGFR

MNT: a new target for AML. (PubMed, Blood Neoplasia) - "Mnt deletion provoked the apoptosis of MLL::AF9 AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-XL (B-cell lymphoma-extra large) specific). Of note, inducing MNT deletion in a human MLL-rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies."

IO biomarker • Journal • Acute Myelogenous Leukemia • B Cell Lymphoma • Leukemia • Lymphoma • Oncology • Transplantation • BCL2 • BCL2L1 • MCL1 • MYC

Anchored in Resistance: Overcoming Nidogen-2 (NID2) - mediated Immunoresistance in Ovarian Cancer with Ras and Bcl-xl Inhibition (AACR-NCI-EORTC 2025) - "This discrepancy highlights an urgent need to uncover tumor-intrinsic resistance mechanisms that may impair ACT efficacy in OC. To investigate mechanisms of immunotherapy (IT) resistance in OC, we developed OVCAR3-derived cell models resistant to Ipilimumab/Nivolumab in vivo (OV3IE) and to BiTEDs in vitro (OV3R), and established patient-derived organoids (PDOs) from IT responders and non-responders...Pharmacologic inhibition of either pathway - using the pan-Ras inhibitor ADT-007 or Bcl-xl inhibitors (Navitoclax, Venetoclax, A-1331852) - restored cytotoxicity in NID2-high models, including resistant PDOs. NID2 is a tumor-intrinsic driver of IT resistance in OC, acting through Ras activation and Bcl-xl upregulation. NID2 is a tumor-intrinsic driver of IT resistance in OC, acting through Ras activation and Bcl-xl upregulation. It may serve as a predictive biomarker for ACT response. Targeting this pathway, particularly via Bcl-xl inhibitors offers a mechanistically..."

IO biomarker • Oncology • Ovarian Cancer • Solid Tumor • BCL2L1 • MUC16 • NID2

Inhibition of Bcl-xL empowers the antineoplastic activity of TTFields in malignant Glioma in vitro (EANO 2025) - "In addition, flow cytometric analyses revealed that a simultaneous treatment with the Bcl-xL inhibitor A-1331852 and TTFields significantly increased the fraction of annexin V-positive (apoptotic) glioma cells... These data suggest that Bcl-xL inhibition enhances the susceptibility of malignant glioma cells towards TTFields. This effect seems to be, at least in part, due to a caspase-dependent cell death mechanism. Further studies are warranted."

IO biomarker • Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • ANXA5 • BCL2 • BCL2L1 • CASP3 • MCL1

Combined treatment with photodynamic therapy and Bcl-xL inhibition has a predominantly synergistic antineoplastic activity in medulloblastoma in vitro (EANO 2025) - "In this study, we performed a preclinical testing of a combined treatment with 5-ALA-based photodynamic therapy (PDT) and the Bcl-xL inhibitor A-1331852 in vitro.Material and The combination therapy was tested on established, primary cultured and stem-like medulloblastoma cells using MTT assays... PDT in combination with Bcl-xL inhibition had a predominantly synergistic inhibitory effect on the cell viability of a broad panel of medulloblastoma cells. This effect was associated with enhanced cleavage of caspases and energy depletion. Further studies are warranted."

Preclinical • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ANXA5 • BCL2L1 • CASP9 • MYC

Investigating novel radiotherapy-BH3 mimetic combinations in glioblastoma (EANO 2025) - "Overall, we have demonstrated that dependence on BCL-2 family proteins is a vulnerability that can be targeted to improve radiotherapy response in GBM. Furthermore, we have identified a promising BH3 mimetic, A1331852, to use in combination with radiotherapy and have completed a proof-of-concept in vivo study that confirms the potential of BH3 mimetics to improve outcomes for patients with GBM."

IO biomarker • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BCL2 • BCL2L1 • MCL1

The BH3-only protein NOXA is essential for apoptosis induction by BH3-mimetics targeting BCL2 or BCL-XL in DLBCL. (PubMed, Br J Haematol) - "Here, we investigated the underlying mechanisms of inherent resistance to the BCL2i ABT-199 and BCL-XL inhibitor A1331852, focusing on the roles of the principal pro-apoptotic BH3-only proteins NOXA and BIM. Resistance to BCL2i and BCL-XL inhibitors was abrogated by suppression of MCL1 expression. In conclusion, we show that NOXA is essential for the effectiveness of BH3-mimetics targeting BCL2/BCL-XL; in the absence of NOXA, BIM displaced from BCL2/BCL-XL can be bound by MCL1."

IO biomarker • Journal • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1 • PMAIP1

ARL3 Enhances ERα Stability via USP10 Deubiquitination to Promote Endocrine Resistance and Drive Mitochondrial Metabolic Reprogramming in HR+ Breast Cancer. (PubMed, Adv Sci (Weinh)) - "In preclinical models, the small-molecule inhibitor A-1331852 (targeting ARL3) potently suppresses ERα-positive tumor growth and synergizes with endocrine therapies. These findings establish ARL3 as a critical regulator of ERα homeostasis via USP10, highlighting its dual role as a biomarker and ARL3-targeted therapeutic for ERα-positive breast cancer."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • ER

Pseudo-Senescence Induced by Palbociclib Does Not Sensitize Pleural Mesothelioma Cells to Combinations With Classical Senolytics (IASLC-WCLC 2025) - "In mice models of MPM, abemaciclib and palbociclib reduced tumour growth and prolonged overall survival. Methods : We have studied the nature of senescence induced by the CDK4/6 inhibitor palbociclib and the chemotherapeutic drug cisplatin in commercial and patient-derived PM cell line models...We attempted to eradicate palbociclib pre-treated PM cells with conventional senolytics like Navitoclax and Dasatinib...Combining BH3 mimetics like venetoclax (Bcl-2 inhibitor), navitoclax, the specific Bcl-xL inhibitor A-1331852, or the Mcl-1 inhibitor S63845 with palbociclib did not enhance cell death...If palbociclib induces "pseudo-senescence" in mesothelioma, the clinical use of CDK4/6 inhibitors is challenged by the risk of tumour regrowth. Our findings underscore the complexity of therapy-induced senescence and the importance of understanding its nature when assessing the effectiveness of senolytics in specific tumour models."

IO biomarker • Breast Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • BCL2L1

Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia. (PubMed, Mol Oncol) - "To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • BCL2L1

Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer. (PubMed, bioRxiv) - "Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC. B7-H3, PSMA, and STEAP1 targeted ADC therapies combining genotoxic payloads with Bcl-xL inhibitors induce p53-dependant apoptotic cell death in mCRPC, providing a clinically viable strategy for the treatment of advanced prostate cancer."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Oncology • Prostate Cancer • Solid Tumor • BCL2L1 • CD276 • STEAP1

Ex vivo Evaluation of BCL-2 Family Member Dependencies in Multiple Myeloma: Synergistic Combinations and Biomarkers of Sensitivity and Resistance (IMS 2025) - "Ex vivo data were integrated with molecular (WES, RNA-Seq) and clinical data using Fisher's Exact Test (mutations), enrichment analysis (transcriptional data), and adapted univariate Cox models to identify features associated with increased synergy or sensitivity ex vivo. ABBV-467, an MCL-1 inhibitor, was the most potent single agent, with LD50 values in the nanomolar range...The BCL-2 inhibitor venetoclax was highly effective in MM with t(11; 14), gain18q, trisomy 13, mutations in ARID2, XBP1, CYLD and HUWE1, "CD1" and "CD2" subtypes, and those overexpressing BCL2. In contrast, BCL-XL inhibition with A-1331852 showed limited single-agent activity...Interestingly, MCL-1 inhibition + Pom demonstrated increased activity in t(14; 16) samples, and consistent with preclinical data, BCL-2 inhibition synergized with panobinostat... BCL-2 and MCL-1 are the dominant anti-apoptotic BCL-2 family effectors in MM. While MCL-1 inhibition may effectively target..."

IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • ARID2 • BAK1 • BCL2 • BCL2L1 • CD2 • HUWE1 • PTPN11 • XBP1

BCL-xL dependency in chromophobe renal cell carcinoma. (PubMed, Cancer Gene Ther) - "We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • BCL2L1 • CASP3