お知らせ • Apr 24
Abbisko Therapeutics Showcases Six Research Advances Highlighting Pan-KRAS, 4th Generation EGFR, And Synthetic Lethality Approaches
Abbisko Therapeutics announced that the company presented six latest preclinical and translational research findings in poster sessions at the American Association for Cancer Research (AACR) Annual Meeting, held from April 17 to 22, 2026, in San Diego, USA. The presentations span multiple key innovation areas, including the pan-KRAS inhibitor ABSK211, the 4th generation EGFR inhibitor ABK-EGFR-1, the CDK4 selective inhibitor ABK-CDK4, the MTA-cooperative PRMT5 inhibitor ABSK131, as well as a ctDNA-based study investigating resistance mechanisms to the FGFR2/3 inhibitor ABSK061. ABSK211 is a potent, highly selective, and orally bioavailable small-molecule pan-KRAS inhibitor developed by Abbisko Therapeutics. It demonstrates broad inhibitory activity against multiple KRAS mutations, addressing significant unmet medical needs in KRAS-driven cancers. At AACR 2026, Abbisko presented preclinical data for both monotherapy and combination strategies of ABSK211. KRAS mutations are highly prevalent across multiple cancers, including pancreatic (~90%), colorectal (~35%), and lung cancer (~25%). While several pan-KRAS inhibitors have entered clinical development, there remains a critical need for enhanced potency. In preclinical studies, ABSK211 demonstrated: Robust in vitro activity: ABSK211 significantly reduced cell viability across multiple KRAS alterations (including G12, G13, Q61, and WT amplification) at sub-nanomolar to nanomolar concentrations. Meanwhile ABSK211 displayed marginal inhibition in KRAS wild-type cell line with normal copy. Strong in vivo efficacy: Oral administration induced deep tumor regression in multiple KRAS G12V xenograft models, with robust target engagement. Broad mutation coverage: Consistent and significant antitumor activity was observed in models harboring KRAS G12D/C/S and G13D mutations. These findings support the clinical advancement of ABSK211, which is currently undergoing IND-enabling studies. Combination therapy is widely considered a key strategy to improve treatment outcomes in KRAS-mutant cancers. ABSK211 demonstrated synergistic antitumor activity with multiple therapeutic agents: In vitro synergy: Significant anti-proliferative synergy with PRMT5 inhibitors across KRAS mutations; strong synergy observed with EGFR monoclonal antibodies and chemotherapy in KRAS G12D/G12V models. Enhanced in vivo efficacy: Combination regimens with PRMT5 inhibitors, cetuximab, immunotherapies, and chemotherapy showed superior tumor growth inhibition and improved durability compared to monotherapy. These results demonstrate that ABSK211 can significantly enhance antitumor efficacy through multi-mechanistic synergy, supporting its further development in combination strategies. ABK-EGFR-1 is a novel 4th generation EGFR inhibitor developed by Abbisko Therapeutics, specifically designed to target the EGFR C797S resistance mutation. It combines high selectivity with central nervous system (CNS) penetration to address key clinical challenges following resistance to 3rd generation EGFR TKIs. The EGFR C797S mutation is a clinically validated mechanism of resistance to third-generation EGFR TKIs, with an estimated 51,000–146,000 cases annually worldwide. Currently, no approved therapies specifically target this mutation, representing a significant unmet clinical need. Preclinical studies showed that ABK-EGFR-1: Exhibits high selectivity over wild-type EGFR and other kinases. Demonstrates significant in vivo antitumor activity in multiple EGFR C797S-driven xenograft models, effectively inhibiting tumor growth. Possesses excellent blood-brain barrier penetration and favorable drug-like properties. ABK-CDK4 is a highly selective, brain-penetrant small-molecule CDK4 inhibitor developed by Abbisko Therapeutics. It is designed to selectively target CDK4, reduce CDK6-related toxicity, and expand treatment potential for patients with brain metastases. 1st generation CDK4/6 inhibitors (e.g., palbociclib, ribociclib, and abemaciclib) have demonstrated clinical benefit in breast cancer, but CDK6 inhibition is associated with dose-limiting hematologic toxicities. In addition, 20–40% of breast cancer patients develop brain metastases, while current therapies have limited CNS exposure. Preclinical studies showed that ABK-CDK4: High selectivity: Over 50-fold selectivity for CDK4 versus CDK6, potentially reducing CDK6-related toxicity. CNS penetration: Favorable CNS exposure (Kpuu > 0.5) and drug-like properties. Antitumor activity: Effective inhibition of Rb phosphorylation and tumor growth in HR+/HER2- breast cancer models. ABSK131 is a potent and selective small-molecule MTA-cooperative PRMT5 inhibitor developed by Abbisko Therapeutics, targeting MTAP-deleted tumors, and is currently in clinical development. MTAP homozygous deletion occurs in approximately 10–15% of solid tumors and frequently co-exists with oncogenic drivers such as KRAS and EGFR. In addition, MTAP abnormities are associated with poor prognosis following standard-of-care therapies across multiple cancer types. Therefore, there remains a significant unmet need for novel and effective combination therapies centered on MTA-cooperative PRMT5 inhibitor for MTAP-deleted tumors, with the potential to enable precision patient stratification and deliver synergistic therapeutic benefits. Preclinical studies demonstrated that ABSK131 exhibits strong synergistic activity with multiple therapies: KRAS inhibitors: Enhanced tumor growth inhibition in KRAS-mutant, MTAP-deleted models when combined with AMG 510 or ABSK141. EGFR inhibitors: Improved anti-proliferative and in vivo antitumor activity in EGFR-mutant, MTAP-deleted NSCLC models when combined with osimertinib. MAT2A inhibitors: Consistent synergistic effects across multiple tumor models when combined with IDE397. Chemotherapy: Synergistic activity observed both in vitro and in vivo when combined with carboplatin in NSCLC models. ABSK061 is a highly potent and selective small-molecule FGFR2/3 inhibitor developed by Abbisko Therapeutics. It has demonstrated encouraging efficacy and safety in Phase I studies and is currently being evaluated in a Phase II trial for gastric cancer. Acquired resistance remains a major challenge limiting the long-term benefit of targeted therapies. Using ctDNA-based next-generation sequencing (NGS), Abbisko conducted longitudinal genomic analyses comparing baseline and progression samples to elucidate resistance mechanisms to ABSK061: On-target resistance: Polyclonal acquired FGFR2 mutations in the FGFR2 kinase domain were commonly observed in gastric cancer and cholangiocarcinoma. Off-target resistance: FGFR2-Atered NSCLC was prone to develop acquired alterations in genes involved in RTK/RAS pathways. These findings provide important molecular insights into resistance mechanisms and inform the design of future combination and sequential treatment strategies.
