공시 • Apr 20
Ascentage Pharma Group International Presents Four Preclinical Studies Demonstrating Potential Of Combination Therapies At American Association For Cancer Research 2026 Annual Meeting
Ascentage Pharma Group International announced that it will present four preclinical studies in poster format at the American Association for Cancer Research 2026 Annual Meeting, held April 17 to 22, 2026 in San Diego, CA, USA. These posters feature three of the Company’s drug candidates, Olverembatinib (HQP1351), a novel BCR-ABL inhibitor; APG-2449, a FAK/ALK/ROS1 triple tyrosine kinase inhibitor; and APG-5918, a PRC2/EED inhibitor. The four studies demonstrate the breadth and versatility of the pipeline, exploring the therapeutic potential of key assets in combination with other approved treatment options in both hematologic malignancies and solid tumors. The research examines Olverembatinib’s potential beyond its approved use in China for chronic myeloid leukemia (CML), exploring new applications in areas such as endometrial carcinoma and mantle cell lymphoma, including combination approaches with BTK inhibitors. Evaluation of APG-2449 in BRAF-mutant tumors, and APG-5918 in small-cell lung cancer, underscores strategic focus on addressing resistance mechanisms and exploring combination strategies. These preclinical investigations are designed to inform clinical development strategies and complement ongoing global registrational trials. Detailed data presented at AACR 2026 Annual Meeting are summarized below: (Abstract #4583) Multitarget kinase inhibitor Olverembatinib (HQP1351) is efficacious and synergizes with chemotherapy in preclinical models of endometrial carcinoma (EC). EC is the most common gynecologic malignancy in developed countries, with an incidence that is steadily increasing globally. Patients with advanced-stage, high-risk non-endometrioid EC subtypes or recurrent disease have a poor prognosis and limited treatment options. Olverembatinib is a tyrosine kinase inhibitor approved by the National Medical Products Administration of China for the treatment of patients with CML. It targets multiple kinases, including VEGFR1–3, FGFR1–4, Src family kinases, RAF, KIT, RET, and PDGFR. Although BTK inhibitors have transformed MCL treatment, response to monotherapy is limited, and efforts are underway to develop combination therapies. Olverembatinib, an investigational multikinase inhibitor (approved in China for CML), inhibits Src-family kinases (e.g., Lyn, Fyn, YES1) and BTK, which are essential for B-cell receptor signaling and B-cell proliferation, differentiation, and activation. Hypothesizing that dual inhibition of Lyn and BTK pathways could enhance antitumor effects, this study evaluated Olverembatinib in combination with acalabrutinib in preclinical MCL models and explored potential mechanisms of action. Olverembatinib potently inhibited MCL cell proliferation both in vitro and in vivo and showed synergistic effects when combined with acalabrutinib. The combination significantly promoted apoptosis and induced G0/G1 cell cycle arrest. Mechanistically, Olverembatinib inhibited phosphorylation of Lyn and its downstream BTK, while the combination further downregulated NF-kB activity. These data provide a scientific rationale for further clinical evaluation of this novel combination therapy in patients with MCL. (Abstract #1858) FAK inhibition by APG-2449 enhances the antitumor activity of MAPK pathway blockade in BRAF V600E-mutant tumor models. BRAF mutations occur in approximately 4% to 8% of all cancers, most frequently in colorectal cancer, melanoma, and non-small-cell lung cancer. The V600E mutation is the most common and functionally activating form, leading to constitutive activation of the mitogen activated protein kinase signaling cascade. Combined BRAF and MAPK kinase inhibition has shown substantial clinical benefit in BRAF V600Emutant melanoma and colorectal cancer. The results showed selective sensitivity of BRAF V600E-mutant cancer cell lines to APG-2449. APG-2449 suppresses compensatory signaling activation induced by MAPK pathway blockade and synergistically enhances the antitumor activity of dabrafenib + trametinib in preclinical models. These results warrant clinical development of APG-2449 for patients with melanoma or colorectal cancer harboring the BRAF V600E mutation. (Abstract #4500) Embryonic ectoderm development inhibitor APG-5918 synergizes with topoisomerase I inhibitors in preclinical small-cell lung cancer models through epigenetic priming of chemosensitivity. Although small-cell lung cancer initially responds to platinum-based chemotherapy, it rapidly develops resistance, resulting in a poor prognosis. PRC2-mediated epigenetic silencing represses Schlafen 11, a biomarker of sensitivity to DNA-damaging therapies, thereby contributing to treatment resistance. EZH2, the catalytic subunit of PRC2, promotes chemoresistance in part through Schlafen 11 repression. EED, another core PRC2 component, stabilizes the complex and maintains its methyltransferase activity, making it an attractive therapeutic target in small-cell lung cancer. Topoisomerase I inhibitors, such as topotecan and irinotecan, are used in relapsed small-cell lung cancer; however, their efficacy is limited when Schlafen 11 is epigenetically suppressed. APG-5918 is a selective and investigational EED inhibitor that disrupts PRC2 function. This study evaluated the antitumor activity of APG-5918 in combination with topoisomerase I inhibitors in preclinical small-cell lung cancer models. In preclinical small-cell lung cancer models, combination treatment with APG-5918 and topoisomerase I inhibitors synergistically inhibited cell proliferation and induced apoptosis. In vivo, APG-5918 combined with irinotecan demonstrated synergistic antitumor activity in the NCI-H446 small-cell lung cancer cell-derived xenograft model without significant body-weight loss, indicating favorable tolerability. Mechanistically, APG-5918 reduced the repressive histone mark H3K27me3, indicating on-target inhibition of PRC2 activity. Consistent with this effect, APG-5918 treatment increased Schlafen 11 and p21 expression. Notably, treatment with topotecan or SN-38 increased H3K27me3 levels, whereas APG-5918 reduced this effect. Combination treatment further decreased expression of PRC2 core components, suppressed cell-cycle progression, and enhanced DNA damage and apoptotic signaling, supporting a synergistic proapoptotic effect. The findings support clinical investigation of APG-5918 in combination with DNA-damaging agents as a promising therapeutic strategy for small-cell lung cancer. Olverembatinib, APG-2449, and APG-5918 are currently under investigation and have not been approved by the U.S. FDA.