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The KRAS gene, which encodes a guanosine triphosphate (GTPase) protein, is frequently mutated in solid cancers. The KRASG12C mutation aberrantly attenuates GTPase activity, leading to accumulation of the GTP-bound activated form of the KRAS protein and activation of downstream signaling pathways. This genotype occurs in approximately 13% of non-small-cell lung cancers (NSCLCs) and 1% to 3% of colorectal cancers and other solid tumors. In this study, investigational agent APG-1842 was characterized as a potent, selective, and covalent KRASG12C inhibitor that irreversibly and specifically blocks KRASG12C in an inactive guanosine diphosphate (GDP)-bound state and downregulates KRAS-dependent signaling. A RAS-GTP pull-down assay demonstrated that APG-1842 (at a concentration as low as 12 nM) completely blocked GDP-GTP nucleotide exchange, which stabilized an inactive GDP-bound form of KRASG12C and thereby inhibited RAS and RAF binding in KRASG12C-mutant human NSCLC NCI-H358 cells. In these cells, APG-1842 dose dependently inhibited KRAS-dependent signaling target proteins, including phosphorylated extracellular signal-regulated kinase (ERK), S6, and serine/threonine protein kinase Akt (protein kinase B), with a half-maximal inhibitory concentration (IC50) value of 4 nM for ERK1/2 phosphorylation. Using a panel of 18 cancer cell lines representing multiple cancer types in cell viability assays, we found that APG-1842 selectively inhibited cell proliferation in KRASG12C-mutated, but not non-KRASG12C or KRAS wild-type, cell lines. Oral APG-1842 in mice carrying cell-derived NCI-H358 NSCLC subcutaneous xenografts exerted significant antitumor efficacy at doses ranging from 3 to 100 mg/kg, resulting in tumor regression at 30 mg/kg and above. Consistent with the cellular results, APG-1842 dose dependently inhibited ERK1/2 and S6 phosphorylation in xenografts after 6 and 24 hours of treatment, correlating with systemic and tumor drug exposures. Significant antitumor activity of APG-1842 was also confirmed in a panel of 8 KRASG12C-mutated patient-derived xenograft models derived from patient samples of lung, colorectal, and gastric cancers. Collectively, these preclinical results suggest that APG-1842 is a potent, bioavailable, and highly selective KRASG12C inhibitor, laying a foundation for clinical development of this agent for patients with KRASG12C-mutant solid tumors. Citation Format: Shaoulai Gu, Qiang Li, Chao Li, Qixin Wang, Douglas D. Fang, Shaomeng Wang, Dajun Yang, Yifan Zhai. Development of covalent KRASG12C inhibitor APG-1842 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2664.

The BCL-2 inhibitor venetoclax has shown impressive efficacy in patients with chronic lymphocytic leukemia, but its clinical benefits are limited by acquired BCL-2 gene mutations that confer drug resistance. Among acquired mutations, those proximal to BH3 binding motifs (e.g., G101V, D103E, and V156D) have the most significant impact on BCL-2 binding to BH3-only prodeath proteins and BH3 mimetics (e.g., venetoclax). Hence, it is important to identify novel therapeutics that address this emerging unmet need. To this end, we investigated the effect of co-targeting BCL-2 and MDM2-p53 apoptosis pathways in preclinical models of acute lymphoblastic leukemia (ALL) with BCL-2 mutations. We first genetically engineered cell lines that express clinically relevant BCL-2 gene mutations in ALL cell line RS4;11, which shows greater expression of mutants, compared to endogenous wild-type BCL-2 protein. Relative to parental cells, sensitivity to venetoclax and investigational, clinical-stage BCL-2 inhibitor lisaftoclax (APG-2575) in mutant cell lines was reduced 160-fold. Using these BCL-2-inhibitor-resistant cell lines, we assessed the effect of combining lisaftoclax with investigational, clinical-stage MDM2-p53 inhibitor alrizomadlin (APG-115). Alrizomadlin inhibits the MDM2-p53 interaction and activates the prodeath p53 tumor suppressor signaling pathways (Aguilar A et al. J Med Chem 2017). Also potentially consequential was the observation that combining alrizomadlin with lisaftoclax synergistically inhibited proliferation and induced apoptosis in RS4:11 cells carrying G101V, V156D, or D103E mutations. Treatment with this combination also synergistically enhanced antitumor activity in mouse xenograft tumor models derived from RS4:11 cells carrying G101V or V156D mutations. In these animal models, lisaftoclax alone exhibited no or limited activity, with T/C (%; i.e., relative tumor volume of treatment group vs. control) values ranging from 86.40% to 99.15%. In contrast, single-agent alrizomadlin exerted slightly more potent activity, with T/C values ranging from 57.25% to 62.35%. Importantly, the combination of lisaftoclax and alrizomadlin demonstrated synergy, with T/C values ranging from 12.30% to 32.16%. Mechanistically, alrizomadlin likely induced expression of prodeath BCL-2 family proteins BAX, PUMA, and Noxa, which are p53 target genes. Further, lisaftoclax plus alrizomadlin more effectively blocked cell cycle entry into the G2/M phase, resulting in accumulation of sub-G1 apoptotic cells. In summary, our study demonstrates, for the first time, that co-targeting BCL-2 and MDM2-p53 apoptosis pathways overcame resistance to BCL-2 inhibitors conferred by acquired BCL-2 gene mutations, potentially offering a viable strategy to overcome drug resistance and thus providing a rationale for clinical investigation. Citation Format: Jing Deng, Kaixiang Zhang, Qiuqiong Tang, Xiaojing Huang, Qixin Wang, Na Li, Douglas D. Fang, Dajun Yang, Yifan Zhai. Co-targeting MDM2-p53 and BCL-2 apoptosis pathways overcomes resistance conferred by acquired BCL-2 gene mutations in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3964.

The AML treatment landscape has improved dramatically in the past decade, with improved objective response rates and overall survival after treatment with newly approved targeted therapies. BCL-2 inhibition combined with a hypomethylating agent or low-dose cytosine arabinoside (Ara-C) is also effective in previously untreated elderly patients who are not candidates for standard induction therapy. However, the effect of BCL-2 inhibition is commonly weakened when tumor cells upregulate antiapoptotic protein MCL-1 to escape apoptosis. Thus, combination therapy is introduced to suppress MCL-1 levels. HHT (omacetaxine mepesuccinate) has been widely used in Chinese patients with AML for 30 years. As an inhibitor of protein synthesis, HHT decreases MCL-1. This study investigated the effect of combining clinical stage BCL-2 selective inhibitor APG-2575 with HHT in AML and MDS cells, as well as murine xenograft tumor models. In AML (MV-4-11, OCI-AML-3) and MDS (SKM-1) cell lines, single-agent HHT exerted stronger antiproliferative and apoptogenic activities compared to APG-2575 (as assessed by Cell Titer Glo assay or flow cytometry). When combined, these treatments synergistically inhibited cellular proliferation and induced apoptosis. In a mouse xenograft tumor model derived from MV-4-11 cells, APG-2575 demonstrated limited antitumor activity, with a T/C (Treated/Control tumor volume %) value of 63% whereas HHT showed stronger activity, with T/C equal to 30%. Most importantly, these antitumor effects were potentiated when APG-2575 and HHT were combined, yielding a T/C value of 3% and partial regression in all treated tumors. Mechanistically, BCL-2 inhibition with APG-2575 decreased BCL-2:BIM complexes and but increased MCL-1:BIM complexes, as liberated BIM was re-sequestered by MCL-1. On the other hand, concomitant treatment with HHT abolished induction of MCL-1:BIM complexes. Besides BIM complexes, MCL-1:PUMA and MCL-1:BAK pairings also decreased after exposure to HHT. The decrease in MCL-1 complex coincided with its downregulation at protein levels. Thus, under such an MCL-1-supressed condition facilitated by HHT treatment, the freed proapoptotic proteins (BIM, PUMA, BAK) more potently manifested apoptotic signals triggered by APG-2575. In summary, APG-2575 synergizes with HHT to potentiate antitumor activity in preclinical models of AML/MDS. HHT suppresses MCL-1 protein, preventing or abolishing formation of MCL-1:BIM, MCL-1:PUMA, and MCL-1:BAK complexes, and hence allowing prodeath proteins to fully engage in tumor cell apoptosis induction. Our results provide scientific rationale for clinical development of APG-2575 plus HHT in patients with AML/MDS. Citation Format: Douglas D. Fang, Qiuqiong Tang, Yanhui Kong, Tao Rong, Qixin Wang, Jing Deng, Dajun Yang, Yifan Zhai. BCL-2 inhibitor APG-2575 and homoharringtonine (HHT) synergistically induces apoptosis and inhibits tumor growth in preclinical models of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 981.

Ovarian cancer is one of the deadliest malignancies in women, and up to 70% of patients with epithelial ovarian cancer have FAK overexpression, amplification, or activation. FAK plays an important role in cellular migration, growth factor signaling, cell cycle progression, cellular survival and chemoresistance. This biomarker is also significantly associated with higher tumor stage, metastasis, and shorter overall survival in patients with ovarian cancer. Inhibition of FAK is therefore emerging as a promising treatment target. APG-2449 is a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor. In this study we investigated antitumor activity of APG-2449 combined with standard-of-care chemotherapeutics in ovarian cancer in the preclinical setting. In a mouse xenograft tumor model derived from ovarian cancer cell line OVCAR-3, which was resistant to platinum-based therapies, APG-2449 combined with paclitaxel, and paclitaxel plus carboplatin, synergistically enhanced antitumor activity, whereas the chemotherapeutics showed no activity. Synergistic antitumor activity was also observed in multiple patient-derived xenograft (PDX) models derived from women with chemoinsensitive ovarian cancer, which also frequently expresses high levels of FAK. By comparing gene expression profiles of PDX tumors obtained from responders and nonresponders to the combined therapy, we identified CD44 (a marker for cancer stem cells) as a potentially predictive biomarker. Western blot analysis confirmed higher protein levels of CD44 in pretreated tumors of responders. Interestingly, downregulation of CD44 levels was observed in combination-treated tumors, suggesting that these combinations reduced cancer stem cell populations in ovarian cancer. Accordingly, in ovarian cancer cells exposed to APG-2449 alone or combined with paclitaxel, numbers of cells positive for CD44 or aldehyde dehydrogenase 1 (ALDH1; another marker for cancer stem cells) decreased in a dose-dependent manner. In summary, our data suggest that FAK inhibition by APG-2449 sensitizes ovarian tumors to chemotherapeutics in preclinical tumor models of ovarian cancer. The synergistic antitumor activity was mediated by downregulation of CD44+ or ALDH1+ cancer stem cell populations. These findings encourage clinical development of APG-2449 in combination with chemotherapies for treatment of ovarian cancer. Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Kaixiang Zhang, Chunhua Xu, Xu Fang, Qixin Wang, Dajun Yang, Yifan Zhai. Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 968.

AML accounts for 80% of acute leukemias in adults. FLT3 gene mutations are observed in approximately 30% of patients with AML and augur a poor prognosis. Despite antitumor effects of selective FLT3 inhibitors, resistance to these agents continues to pose a formidable clinical challenge. The expression of pro-survival protein BCL-2 is frequently dysregulated, conferring resistance to FLT3 inhibitors, in AML. In this study, we explored the combination of clinical stage multikinase inhibitor HQP1351 (which also targets FLT3) and BCL-2-selective inhibitor APG-2575 in preclinical models of FLT3-mutant AML. Antileukemic activity of HQP1351 was first examined using AML cell lines MV-4-11 and MOLM-13, which harbor FLT3-internal tandem duplication (FLT3/ITD) mutations. In both cell lines, HQP1351 dose-dependently induced cellular apoptosis, APG-2575 also induced apoptosis, and their combination synergistically induced this process. In particular, treatment of subcutaneous MV-4-11 xenograft tumors in nude mice with HQP1351 10 mg/kg significantly suppressed tumor growth, with a tumor growth inhibition (TGI) of 72.4%. This antitumor effect was potentiated when APG-2575 was combined with HQP1351, resulting in a TGI of 97.2%. The combination also improved survival of tumor-bearing mice with a systemic MOLM-13 model compared to either agent alone. Mechanistically, HQP1351 likely inhibited phosphorylation of FLT3 and its downstream signaling pathways, including phosphorylation of AKT, ERK1/2 and STAT5. Taken together, these findings indicate that the antileukemic activity of olverembatinib can be ascribed to on-target inhibition. Single-agent APG-2575 agent triggered cellular apoptosis, as evidenced by cleavage of caspase-3 cleavage and poly(ADP-ribose) polymerase-1 (PARP-1) activation, which are considered hallmarks of apoptosis. Consequently, APG-2575 treatment also increased expression of another antiapoptotic protein (MCL-1), upregulation of which is a pivotal mechanisms of resistance to BCL-2 inhibitors. Notably, HQP1351 substantially decreased cellular MCL-1 expression when combined with APG-2575, further enhancing apoptosis.Taken together, our data suggest that FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-mutant AML. The results provide scientific rationale for clinical development of HQP1351 combined with APG-2575 in patients with FLT3-ITD-mutant AML. Citation Format: Douglas D. Fang, Hengrui Zhu, Qiuqiong Tang, Qixin Wang, Na Li, Xu Fang, Ping Min, Guangfeng Wang, Dajun Yang, Yifan Zhai. FMS-like tyrosine kinase 3 (FLT3) inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 in preclinical models of FLT3-mutant acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1096.

HQP1351 is a novel, orally bioavailable multi-kinase inhibitor targeting BCR-ABL, KIT, and FLT3. Currently, HQP1351 is in phase II clinical trials in relapsed and refractory chronic myeloid leukemia (CML) patients by targeting BCR-ABL. Besides, HQP1351 inhibits both wild-type and mutant FLT3 in kinase binding assay. APG-115 is another clinical stage, small molecule MDM2 antagonist. In the present study, we explored the antitumor effect of the combination of HQP1351 and APG-115, and the molecular mechanism in FLT3-ITD and TP53 wild-type acute myeloid leukemia (AML) in the preclinical setting. First, the effect of HQP1351 as single agent on cell viability in FLT3-ITD mutant and TP53 wild-type human AML cell lines, including MV-4-11 and MOLM-13. Second, antitumor activity of the combination was investigated in systemic and subcutaneous xenograft models in NOD/SCID mice derived from these cells. The results showed that HQP1351 alone exhibited potent antiproliferative activity in both cell lines in vitro, with nanomolar IC50 values. The activity was enhanced in the combination treatment with APG-115. In vivo, HQP1351 single agent demonstrated significant antitumor activity evidenced by a markedly reduction of tumor burden (i.e., CD45+ human tumor cells) in systemic MOLM-13 xenograft model. Treatment with HQP1351 at 3, 10 and 30 mg/kg significantly prolonged mice survival with median survival of 20.5 days, 26.0 days and 35 days, respectively, compared with 18 days in the control group. In subcutaneous MV-4-11 xenograft model, treatment with HQP1351 or APG-115 single agents achieved T/C values of 28.6% and 59.6%, respectively. The combination achieved synergistic antitumor activity with a T/C value of 13.4%. The benefit of the combination was also demonstrated in systemic MOLM-13 xenograft model. Mechanistically, the combined treatment synergistically downregulated p-FLT3, p-ERK, p-STAT5 and anti-apoptotic protein MCL-1, and thus enhanced antitumor effect. Taken together, our data provide scientific rationale for clinical development of the combination of HQP1351 and APG-115 in FLT3-ITD mutant and TP53 wild-type AML patients. Citation Format: Douglas D. Fang, Qiuqiong Tang, Qixin Wang, Na Li, Xu Fang, Jiaxing Gu, Yanhui Kong, Tao Rong, Guangfeng Wang, Dajun Yang, Yifan Zhai. Synergy of tyrosine kinase inhibitor HQP1351 and MDM2-P53 antagonist, APG-115, in preclinical models of FLT3 mutant and TP53 wild-type acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4217.

Blockade of the checkpoint inhibitor programmed death 1 (PD-1) has gained big success in cancer therapy. However, the response rate of anti-PD1 agents remains low. Molecularly targeted agents offer selectivity and high tumor response rates, but patients develop resistance to these drugs inevitably. Combinations of targeted agents and immunotherapy provide new opportunities to improve cancer treatments. Recent studies found that p53 activation in the myeloid linage suppressed alternative (M2) macrophage polarization and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may further augment antitumor immunity elicited by anti-PD-1 therapy. APG-115 is an orally active, selective, small molecule inhibitor of the MDM2-p53 protein-protein interaction. APG-115 acts as an antitumor agent by activating the p53 tumor suppressor in p53 wild-type tumors. However, its role in regulating immune responses remained unknown. In this study, we investigated the role of APG-115 in immune modulation both in vitro and in vivo. Enhanced antitumor activity was first demonstrated in p53 wild-type MH-22A, p53 mutant MC38, and p53 knockout (p53-/-) MH-22A syngeneic tumor models after the combination treatment of APG-115 and anti-PD-1 antibody. Despite differential changes in tumor-infiltrating leukocytes, including an increase in cytotoxic CD8+ T cells in the p53 wild-type tumors and an increase in proinflammatory M1 macrophages in the p53 mutant tumors, the combination treatment consistently reduced immunosuppressive M2 macrophages in the tumor microenvironment regardless of p53 status of tumor cells. In addition, in vitro, the treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21 gene expression, as well as a decrease in M2 macrophages population and reduction of c-MYC and M2-related gene expression. Moreover, enhanced M1 macrophage polarization in the spleen was also observed in naïve mice treated with APG-115. Furthermore, APG-115 increased production of multiple proinflammatory cytokines, including IFN-γ, TNF-α, IL-2 and IL-6, in stimulated T cells. Collectively, for the first time, our findings suggest that p53 activation by a pharmacological MDM2 inhibitor enables reversal of immunosuppressive tumor microenvironment and enhance antitumor immunity independently of p53 status of tumors. Specifically, in complementary to PD-1 blockade that predominantly activates cytotoxic CD8+ T cell populations, APG-115 primarily targets tumor-associated macrophages. Collectively, our data provide a rationale for applying the combination of APG-115 plus PD-1 blockade to a broader patient population with p53 mutant tumors. Accordingly, a clinical trial of APG-115 in combination with pembrolizumab in metastatic melanoma patients regardless of p53 status has been initiated in the USA. Citation Format: Douglas D. Fang, Qiuqiong Tang, Yanhui Kong, Qixin Wang, Jiaxing Gu, Xu Fang, Peng Zou, Tao Rong, Jingwen Wang, Dajun Yang, Yifan Zhai. Activation of p53 in the tumor microenvironment by MDM2 inhibitor APG-115 synergizes with PD-1 blockade independently of p53 status of tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3192.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are among the most prevalent B-lymphocyte neoplasms with Bruton’s tyrosine kinase (BTK) often found abnormally activated in these patients. BTK inhibitor ibrutinib has showed proven efficacy in both indications, but its clinical application is limited to gradually acquired resistance. Recent studies reported that ibrutinib-resistant cells exhibited higher BCL-2 expression and therefore increase their sensitivity to BCL-2 inhibitors. In this study, using a BCL-2 selective inhibitor APG-2575, we asked whether its combination with ibrutinib enhanced antitumor activity in FL and DLBCL in preclinical studies. Indeed, the combination treatment with APG-2575 and ibrutinib synergistically enhanced antitumor activity in DOHH2 cell-derived FL xenograft models. Similarly, enhanced activity was achieved in DLBCL xenograft models derived from OCI-LY1 cells. Interestingly, in OCI-LY1 xenografts, the combination treatment achieved a 100 % response rate, which include partially (PR) and complete tumor regression (CR), with ~80 % of CR and ~20 % of PR recorded. Durable response was continuously observed till the end of the study after dose suspension. Pharmacokinetic studies revealed that there were no significant changes in drug concentrations between single agents and the combination treatment, suggesting there was no drug-drug interaction between these two agents. On-target pharmacodynamic (PD) modulations of BTK and apoptosis pathways were observed in corresponding tumor tissues co-treated with ibrutinib and APG-2575. An increase in the levels of cleaved PARP-1 protein was observed under the combination treatment suggesting enhanced induction of apoptosis occurred, which may be the biological event contributing to the synergistic effect of the combination treatment. In summary, our study suggests that APG-2575 may be applied to the combination therapy with ibrutinib in the treatment of FL and DLBCL. Citation Format: Douglas D. Fang, Guoqin Zhai, Shoulai Gu, Ran Tao, Qiuqiong Tang, Ping Min, Qixin Wang, Dongmei Yang, Jiaxing Gu, Yinfeng Li, Dingxiong Chen, Jiajun Li, Guangfeng Wang, Dajun Yang, Yifan Zhai. BCL-2 selective inhibitor APG-2575 synergizes with BTK inhibitor in preclinical xenograft models of follicular lymphoma and diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2058.

Effective treatments are urgently needed for elderly acute myeloid leukemia (AML) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients as only 10-25% of the population respond to standard therapies and resistance often occurred. Concurrent overexpression of anti-apoptotic BCL-2 gene and proto-oncogene MYC are frequently found in AML and DLBCL and this molecular characteristic is associated with poor prognosis of patients. CDK9 controls non-ribosomal transcription of genes including MYC and MCL-1. Dysregulation in the CDK9 pathway had been reported in AML and DLBCL, making it an attractive target for the combination with BCL-2 inhibitor to achieve more effective therapy. To test the above hypothesis, in this study, we applied the combination of APG-2575 with a CDK9 inhibitor (alvocidib or dinaciclib) to preclinical tumor models. APG-2575 is a novel, orally bioavailable BH3-mimetic that selectively inhibits BCL-2, but not BCL-xL or MCL-1. After the treatment, synergistic effect of the combination treatment was demonstrated in mice bearing xenograft tumors of human AML or DLBCL. Specifically, in xenograft tumor models derived from human DLBCL cell line U2932, the treatment with APG-2575, alvocidib, or dinaciclib single agent for 22 days exhibited antitumor activity with T/C values of 20-50% (T/C value, average tumor volumes in treatment group vs. the vehicle control group). The combination treatment achieved substantial antitumor activity with T/C value of 5%. All animals in the combination groups showed either partial or complete tumor regression whereas none in the single arms. Similar synergistic antitumor activity of the combination treatment was consistently observed in the myelodysplastic syndrome SKM-1 and AML OCI-AML-3 xenograft models. Taken together, our data suggest that APG-2575 and CDK9 inhibition combination has a potential therapeutic application in treatment of patients with AML and DLBCL. Citation Format: Douglas D. Fang, Ran Tao, Qiuqiong Tang, Shoulai Gu, Guoqin Zhai, Jiajun Li, Qixin Wang, Xu Fang, Na Li, Dajun Yang, Yifan Zhai. Synergistic effect of BCL-2 inhibitor APG-2575 and CDK9 inhibitor in acute myeloid leukemia and DLBCL preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3068.