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  • ||||||||||  AZD5991 / AstraZeneca, A-1331852 / AbbVie, ML210 / University of Sydney
    Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay (Section 23) -  Mar 5, 2024 - Abstract #AACR2024AACR_6716;    
    Our analysis also reveals the importance of appropriate dose selection and analytical metrics for reliably measuring combined effects. In conclusion, the PRISM platform's multiplexed cell line screening is a robust method for characterizing rationally designed drug combinations, offering a systematic approach to enhance the precision of combination therapy development in cancer care.
  • ||||||||||  A-1331852 / AbbVie
    Investigation of BH-3 mimetics as radiosensitizing agents in glioblastoma (Section 28) -  Mar 5, 2024 - Abstract #AACR2024AACR_2662;    
    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 RT and have completed a proof-of-concept in vivo study that confirms the potential of BH3 mimetics to improve outcomes for patients with GBM.
  • ||||||||||  A-1331852 / AbbVie
    Journal:  Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth. (Pubmed Central) -  Jan 18, 2024   
    Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan...Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity.
  • ||||||||||  Jakafi (ruxolitinib) / Novartis, Incyte, A-1331852 / AbbVie
    BCL-Xl Represents a Novel Therapeutic Target in Type 2 Mutant Calr-Driven Myeloproliferative Neoplasms (SDCC - Halls G-H) -  Nov 3, 2023 - Abstract #ASH2023ASH_4080;    
    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.
  • ||||||||||  Identification of vulnerabilities for targeting BCL-2 family members in T-Cell Acute Lymphoblastic Leukemia (SDCC - Halls G-H) -  Nov 3, 2023 - Abstract #ASH2023ASH_2023;    
    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.
  • ||||||||||  DT2216 / Dialectic Therap, A-1331852 / AbbVie, navitoclax (ABT 263) / AbbVie
    Journal, IO biomarker:  Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer. (Pubmed Central) -  Jun 19, 2023   
    However, we found that BCL2L1 copy number variations (CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute
    BCL-2/BCL-XL INHIBITION INDUCES APOPTOSIS AND CIRCUMVENTS VENETOCLAX RESISTANCE IN TP53-MUTATED ACUTE MYELOID LEUKEMIA (Poster area) -  May 12, 2023 - Abstract #EHA2023EHA_1845;    
    P2
    In contrast, our BH3 mimetic drug screening results demonstrated that the dual inhibition of BCL-2 and BCL-XL by navitoclax is capable of inducing apoptosis in myeloid blast cells regardless of TP53 mutation status. However, larger patient cohorts and more extensive functional analysis of the anti/pro-apoptotic dependencies in this patient group is warranted.
  • ||||||||||  A-1331852 / AbbVie, Lynparza (olaparib) / Merck (MSD), AstraZeneca
    Journal, PARP Biomarker, IO biomarker:  B-cell lymphoma extra-large (Bcl-xL) is a promising drug target in Merkel cell carcinoma. (Pubmed Central) -  Mar 30, 2023   
    However, larger patient cohorts and more extensive functional analysis of the anti/pro-apoptotic dependencies in this patient group is warranted. Bcl-xL, which is highly expressed in MCC, appears to be an attractive therapeutic target for the treatment of this tumor; especially since the effect of specific Bcl-xL inhibitors is synergistically enhanced by simultaneous PARP inhibition.
  • ||||||||||  A-1331852 / AbbVie, navitoclax (ABT 263) / AbbVie
    Targeting endogenous and therapy-induced dependence on BCL-XL in high grade serous ovarian carcinoma (Section 16; Poster Board #23) -  Mar 14, 2023 - Abstract #AACR2023AACR_8398;    
    Based on BH3 profiling, flow cytometry-based cell death analysis and colony formation assays, we found that HGSOC cells are particularly sensitive to BCL-XL inhibitors including the first-generation BH3 mimetics ABT-263 and A1331852 as well as novel proteolysis-targeting chimeras (PROTACs) that degrade BCL-XL...We also detected BCL-XL dependence in ovarian cancer tumorigenesis models utilizing human fallopian tube secretory epithelial cells, the putative cell of origin for HGSOC. Overall, we find that BCL-XL inhibitors, especially PROTACs, can safely enhance the chemosensitivity of HGSOC cells in vitro and in vivo and may therefore prevent tumor recurrence in women diagnosed with this disease.
  • ||||||||||  Zepzelca (lurbinectedin) / PharmaMar, Jazz
    Lurbinectedin exhibits combinatorial activity with BCL2/BCL2L1 inhibitors in vitro and in vivo by modulation of MCL1 expression (Section 16; Poster Board #17) -  Mar 14, 2023 - Abstract #AACR2023AACR_8393;    
    Correspondingly in vivo, enhancement in the efficacy of lurbinectedin was observed in combination with venetoclax in SCLC models, while in solid tumor models other than SCLC the combination with a specific BCL2L1 inhibitor enhanced efficacy. Collectively, these data identify MCL1 as a specific lurbinectedin target and suggest that combinations that target other pro-survival proteins may represent a viable strategy to enhance the anti-tumor activity of lurbinectedin.
  • ||||||||||  A-1331852 / AbbVie
    Combined treatment with the epigenetic drug CM272 and an anti-BCL-XL proapoptotic drug sensitizes solid tumors to immune checkpoint blockade (Section 22; Poster Board #20) -  Mar 14, 2023 - Abstract #AACR2023AACR_7454;    
    In vivo, the triple combination CM272, A1331852 (BCL-XL inhibitor) and an anti-PD-1 moAb significantly reduced tumor growth and increased overall survival in three subcutaneous lung cancer models (LLC, 393P, Lacun-3) in comparison to double treatments...The mechanisms underneath the antitumor responses include the modulation of the energy metabolism in tumor cells, leading to cell death boosted by an anti-BCL-XL pro-apoptotic drug, along with fostering the immune system to generate an efficient anti-tumor response assisted by ICB. This study reveals the potential of epigenetic therapeutics to treat and cure patients with solid tumors.
  • ||||||||||  JQ-1 / Roche, S63845 / Servier, Novartis, HitGen, A-1331852 / AbbVie
    Activating programmed cell death pathways to improve therapy in glioblastoma multiforme (GBM) () -  Jan 13, 2023 - Abstract #LCC2023LCC_35;    
    We found that a BCL-XL plus an MCL-1 inhibitor potently cooperate with inducers of ferroptosis in killing U251 cells. Overall, these findings demonstrate the potential of dual targeting of distinct programmed cell death pathways in GBM and may guide the utility of BCL-XL inhibitors and inducers of ferroptosis with standard of care treatment for improved therapies for GBM.
  • ||||||||||  A-1331852 / AbbVie, acalisib (GS-9820) / Gilead, navitoclax (ABT 263) / AbbVie
    Journal, PARP Biomarker, IO biomarker:  Bcl-xL inhibition radiosensitizes PIK3CA/PTEN wild-type triple negative breast cancers with low Mcl-1 expression. (Pubmed Central) -  Nov 19, 2022   
    In vivo, ABT-263 or A-1331852 in combination with RT decreased tumor growth and increased tumor tripling time (p < 0.0001) in PIK3CA/PTEN wild-type TNBC cell line and patient-derived xenografts. Collectively, this study provides the preclinical rationale for early phase clinical trials testing the safety, tolerability, and efficacy of Bcl-xL inhibition and RT in women with wild-type PIK3CA/PTEN wild-type TNBC at high risk for recurrence.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, onametostat (JNJ-64619178) / J&J
    Inhibition of PRMT5 Increases Sensitivity to BH3 Mimetics in Aggressive B Cell Malignancies (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_5790;    
    P1
    The DLBCL cell lines (HBL1, TMD8, RI-1, OCI-Ly1, Karpas 422, SUDHL4, Toledo), double hit lymphoma (DHL) patient-derived xenograft (PDX) cell lines (DW19), mantle cell lymphoma (MCL) cell lines (Mino, Jeko-1), T cell acute leukemia (T-ALL) cell line (Jurkat) and Burkitt lymphoma (BL) cell line (Raji) were used to investigate the in vitro anti-cancer activity of JNJ-64619178 (Janssen Pharmaceuticals) and BH3 mimetics (venetoclax [BCL2i], S63845 [MCL-1i] and A1331852 [BCL-xLi], Selleckchem). The combination of a PRMT5 inhibitor with BH3 mimetics, especially venetoclax, is worthy of further exploration as a potential therapeutic strategy for DLBCL and MCL.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie
    The Flavonoid Brusatol Induces Apoptosis in Aggressive Lymphoma Cells and Exhibits Synergistic Effect with Venetoclax (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_3037;    
    Despite the available chemoimmunotherapy R-CHOP, one third of DLBCL patients still have primary refractory disease or relapse, and the incidence of these lymphomas continuously increases...Furthermore, co-treatment of Brusatol with inhibitors of Bcl-2 (Venetoclax), Bcl-XL (A-1331852), Mcl-1 (S63845), BTK (Ibrutinib), PI3K (Idealisib), Myc (EN4, JQ1), respectively, was performed in the same four cell lines and Annexin V levels were measured after 24h...Additionally, the combination of Brusatol with Venetoclax results in enhanced induction of apoptosis. Thus, our study suggests that Brusatol, alone or in combination with Venetoclax, represents a very interesting agent for further development of novel anti-lymphoma therapies.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie
    Erythroid/Megakaryocytic Differentiation Confers BCL-XL Dependency and Venetoclax Resistance in Acute Myeloid Leukemia (ENMCC - 343-345) -  Nov 4, 2022 - Abstract #ASH2022ASH_1337;    
    Combining BCL-XL inhibition with the JAK inhibitor ruxolitinib, the BCL-2 inhibitor venetoclax, or the hypomethylating agent azacitidine showed potential for more durable responses both in a 3-day ex vivo assay as well as long-term treatments spanning over a month. Collectively, our results suggest targeting BCL-XL as a potential therapy option in erythroid and megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.
  • ||||||||||  erastin - Whitehead Institute for Biomedical Research, Dana / Farber Cancer Institute, Columbia University, Prolexys, A-1331852 / AbbVie, navitoclax (ABT 263) / AbbVie
    TARGETING YAP-MEDIATED HEPATIC STELLATE CELL DEATH SUSCEPTIBILITY AND SENESCENCE FOR TREATMENT OF LIVER FIBROSIS (Room 202) -  Oct 23, 2022 - Abstract #AASLD2022AASLD_431;    
    Targeting YAP-mediated HSC death susceptibility by systematic administration of ferroptosis inducer or Bcl2 inhibitors failed to improve liver fibrosis. However, depleting YAP in a MF-HSC specific manner induced HSC senescence and protected against liver fibrosis.
  • ||||||||||  A-1331852 / AbbVie
    Journal:  Bcl-xL activity influences outcome of the mitotic arrest. (Pubmed Central) -  Oct 4, 2022   
    Using normal fibroblasts and several cancer cell types we determined two critical doses, T1 and T2, of mitotic inhibitors (nocodazole, Taxol, and vinorelbine)...Combined treatment with MT drugs and highly specific Bcl-xL inhibitors A-1155643 or A-1331852 allows achieving 100% DiM in a time significantly shorter than maximal duration of mitotic arrest in all types of cultured cells tested...Thus sequential use of mitotic inhibitors and inhibitors of Bcl-xL anti-apoptotic protein will be efficient only if the Bcl-xL inhibitor will be added before mitotic slippage occurs or soon afterward. The combined treatment proposed might be an efficient approach to anti-cancer therapy.
  • ||||||||||  A-1331852 / AbbVie
    Journal:  BID- and BAX-mediated mitochondrial pathway dominates A-1331852-induced apoptosis in senescent A549 cells. (Pubmed Central) -  Sep 14, 2022   
    In addition, A-1331852 also dissociated the binding between BCL-xL and BAX, eventually leading to BAX oligomerization in the mitochondria, and resulting in apoptosis via the mitochondrial pathway. In conclusion, our data demonstrate for the first time that A-1331852 promotes apoptosis of senescent A549 cells by influencing the interaction between BCL-xL and tBID and that between BCL-xL and BAX.
  • ||||||||||  Review, Journal:  Anticancer effects of putative and validated BH3-mimetic drugs in head and neck squamous cell carcinomas: An overview of current knowledge. (Pubmed Central) -  Jul 28, 2022   
    The remaining 39 preclinical studies investigated cell lines and/or xenograft models involving the use of six validated BH3-mimetics (A-1210477, A-1331852, ABT-737, navitoclax, S63845, venetoclax) and six putative BH3-mimetics (ApoG2, gossypol, obatoclax, sabutoclax, TW-37, and YC137)...In conclusion, although clinical data are still insufficient to evaluate the anticancer effects of BH3-mimetics in head and neck squamous cell carcinomas, promising results in preclinical settings were observed concerning induction of cell death and inhibition of tumour growth. Therefore, further clinical trials are highly encouraged.
  • ||||||||||  JQ-1 / Roche, RSL3 / Stanford University
    Journal, PARP Biomarker, IO biomarker:  BH3 mimetic drugs cooperate with Temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells. (Pubmed Central) -  Jul 23, 2022   
    We found that a BCL-XL or an MCL-1 inhibitor potently cooperates with inducers of ferroptosis in killing U251 cells. Overall, these findings demonstrate the potential of dual targeting of distinct PCD signalling pathways in GBM and may guide the utility of BCL-XL inhibitors and inducers of ferroptosis with standard of care treatment for improved therapies for GBM.
  • ||||||||||  carfilzomib / Generic mfg.
    CARFILZOMIB RESISTANCE IS ASSOCIATED WITH SIGNIFICANT DEREGULATION OF THE BH3 FAMILY PROTEINS () -  May 13, 2022 - Abstract #EHA2022EHA_1953;    
    Decreased sensitivity to the BCL-2 inhibitor venetoclax as well as to the BCL-xL inhibitor A1331852 was observed in resistant KMS12PE cells...This is further emphasized by the coherent deregulation of BCL-xL and BAK throughout carfilzomib exposed carfilzomib resistant cell lines when compared to their sensitive cell line variants. Moreover, BH3 profiling indicates a change in dependency on anti-apoptotic BH3 protein in carfilzomib resistant vs. sensitive MM cell lines.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, HitGen, A-1331852 / AbbVie
    PREDICTING THE RESPONSE OF DLBCL CELLS TO BH3-MIMETICS USING SYSTEMS BIOLOGY () -  May 13, 2022 - Abstract #EHA2022EHA_1690;    
    Using a combination of in silico and in vitro experiments, we show that a computational model can predict the sensitivity of a cell to targeted therapies. Future work will test the ability of the model to predict patient responses to targeted therapies in order to enable a personalised medicine approach.
  • ||||||||||  AZD4320 / AstraZeneca
    THE DUAL BCL-2 AND BCL-XL INHIBITOR AZD4320 SHOWS ON-TARGET ACTIVITY IN ALL AND ACTS SYNERGISTICALLY WITH MCL-1 INHIBITION () -  May 13, 2022 - Abstract #EHA2022EHA_596;    
    Aims In this study, the anti-leukemia activities of the dual BCL-2 and BCL-XL inhibitor AZD4320 and of MCL-1-selective AZD5991 were evaluated and compared to the effects of other BH3-mimetics (BCL-2-selective venetoclax, BCL-XL-selective A-1331852 and MCL-1-selective S63845)...Importantly, the highest synergism was found at low concentrations of both inhibitors, suggesting efficacy at moderate concentrations, which could potentially be achieved in vivo . Conclusion In summary, our study demonstrates sensitivity, on-target activity and synergism of the dual BCL-2 and BCL-XL inhibitor AZD4320 with inhibition of MCL-1, thereby providing strong evidence for further clinical evaluation in ALL.
  • ||||||||||  A-1331852 / AbbVie
    Journal, PARP Biomarker:  BAK plays a key role in A-1331852-induced apoptosis in senescent chondrocytes. (Pubmed Central) -  May 12, 2022   
    Live-cell fluorescence resonance energy transfer showed that A-1331852 detached the binding of Bcl-xL to BAK and promoted the oligomerization of BAK on the mitochondrial membrane. In conclusion, this study provides the first evidence that A-1331852 selectively promotes apoptosis in senescent chondrocytes by interfering with the interaction between Bcl-xL and BAK.
  • ||||||||||  S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
    Smac mimetic and BH3 mimetics sensitize rhabdomyosarcoma spheroids towards NK cell killing () -  May 9, 2022 - Abstract #CIMT2022CIMT_260;    
    Using the related BH3 mimetic compound A1331852, only RH30 spheroids showed an increased killing by NK cells...The killing seems to be independent of TRAIL but highly dependent on caspase activation. Therefore, combining a cell death sensitizing agent with cytotoxic immune cells, opens the possibility for a novel cellular immunotherapeutic approach.
  • ||||||||||  A-1331852 / AbbVie
    Journal:  Targeting entry into mitochondria for increased anticancer efficacy of BCL-X-selective inhibitors in lung cancer. (Pubmed Central) -  Apr 26, 2022   
    Our results indicated that NA-2a was selectively enriched in mitochondria transported by organic-anion-transporting polypeptide (OATP) transporters, which altered the permeability of the mitochondrial membrane, thereby promoting the entrance of A-1331852 to mitochondria and enhancing its disruption of the BIM-BCL-X complex, which finally led to the increased anticancer activity in vitro and in vivo. Collectively, our data provided overwhelming evidence that the combination of NA-2a and A-1331852 could be used as a promising synergistic therapeutic agent in NSCLC therapy.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
    Journal:  Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL. (Pubmed Central) -  Apr 7, 2022   
    The effect of combining BCL-2 and MCL-1 inhibition by venetoclax and S63845 was evaluated in vivo and strongly enhanced anti-leukemia activity was found in a pre-clinical patient-derived xenograft model. Our study offers in-depth molecular analysis of mutual substitution of BCL-2 family proteins in acute lymphoblastic leukemia and provides targets for combination treatment in vivo and in ongoing clinical studies.
  • ||||||||||  omipalisib (GSK2126458) / GSK, A-1331852 / AbbVie, Synribo (omacetaxine mepesuccinate) / Stragen, Teva
    Development of the drug efficacy testing in ex vivo 3D cultures (DETECT) platform and its application to functional precision medicine in ovarian cancer (Section 26) -  Mar 9, 2022 - Abstract #AACR2022AACR_3987;    
    Combination screening revealed that Carboplatin and A-1331852, a BCL-XL inhibitor, showed increased efficacy in 3 of the 5 tested patient samples. In conclusion, our 3D HT-drug testing assay DETECT with a combination screening capability could in the future be useful for guiding individualized treatment in a clinical setting as well as for identifying existing and emerging drugs and drug combinations for repurposing in OC.
  • ||||||||||  peposertib (M3814) / EMD Serono
    Peposertib-induced senescence primes irradiated p53 wild-type cancer cells for clearance by both immune cells and senolytic drugs (Section 10) -  Mar 9, 2022 - Abstract #AACR2022AACR_3060;    
    Our experiments revealed that selective inhibition of DNA-PK in irradiated p53 wild-type cancer cells provides a powerful mechanism for induction of senescent cancer cells with an immunostimulatory secretory phenotype in vitro. In addition, these cells can be selectively targeted by senolytic agents, suggesting that triple combination radiotherapy with DNA-PK inhibitors and senolytics could offer a potential new approach to the treatment of locally advanced tumors.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, AZD5991 / AstraZeneca, A-1331852 / AbbVie
    Pre-clinical investigations utilizing Bcl2 inhibitors in glioblastoma (Section 23) -  Mar 9, 2022 - Abstract #AACR2022AACR_2690;    
    Our preclinical data suggests synergism of Bcl-2 protein inhibitors in GBM cells, both TMZ-naïve and TMZ-resistant. Our ongoing research is investigating the biological relevance of Bcl-2 in conjugation with other tumor suppressor proteins, in vitro and in vivo.
  • ||||||||||  Journal:  Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells. (Pubmed Central) -  Feb 19, 2022   
    FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-X-selective inhibitors such as S63845 and A1331852...In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.
  • ||||||||||  Targeting Bclxl Mitigates Mcl1 Chemoresistance in Multiple Myeloma (GWCC - Hall B5, Level 1) -  Nov 5, 2021 - Abstract #ASH2021ASH_4296;    
    A combinatorial approach targeting Mcl1 and BclxL induced immediate and significant anti-MM effect both in vitro and ex vivo but proved to be toxic in vivo . Combination of the anti-MM therapeutic panobinostat in combination with S635845 recapitulated the anti-MM activity seen with A1331852 and warrants further evaluation.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, A-1331852 / AbbVie
    Synergistic Activity of BH3-Mimetics By Combined Targeting of Anti-Apoptotic Regulators in B-Cell Precursor ALL (GWCC - B302-B303, Level 3) -  Nov 5, 2021 - Abstract #ASH2021ASH_2195;    
    Taken together, we found heterogeneous responses of BCP-ALL samples to BH3-mimetics antagonizing BCL-2, MCL-1 and BCL-XL. The ability of leukemia cells to adapt their anti-apoptotic dependency from BCL-2 to MCL-1 or BCL-XL can be used as target for combination therapy, demonstrating synergistic activity in PDX samples ex vivo and in vivo .