PO.CL07.04 · 临床研究
选择性SMARCA2（BRM）抑制剂HD-11273联合治疗用于治疗SMARCA4（BRG1）缺陷型癌症
Combination therapy with selective SMARCA2 (BRM) inhibitor HD-11273 for treatment of SMARCA4 (BRG1)-deficient cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
SMARCA2（BRM）和SMARCA4（BRG1）是SWI/SNF染色质重塑复合物的催化亚基，以相互排斥的方式通过其ATP酶结构域调控核小体组成。泛癌分析表明SMARCA4突变发生于所有癌症中，尤其是SMARCA4突变见于8-10%的非小细胞肺癌（NSCLC）病例，提示SMARCA2作为一个潜在的合成致死靶点。多项研究报道，NSCLC中KRAS和SMARCA4的共突变频率约为7.7-10%，其中约39-47%的SMARCA4突变患者携带KRAS突变。且SMARCA4突变型NSCLC患者通常对常规化疗反应不佳。我们选择HD-11273作为临床前候选药物，它通过制备选择性SMARCA2抑制剂HD-10991的特定盐型而展现出改善的物理化学性质。在此，我们报道HD-11273与标准化疗以及目前正在开发的KRAS抑制剂的联合研究。HD-11273单药治疗显著抑制了SMARCA4缺失的A549 CDX模型以及患者来源的癌症类器官（PDO）模型的生长。靶向多种通路的联合治疗被认为对于克服单药治疗的局限性（包括长期治疗产生的耐药）至关重要。为评估治疗获益，我们在携带KRAS和SMARCA4共突变的癌症中测试了我们的选择性SMARCA2抑制剂与KRAS G12C（storasib、adagrasib）、KRAS G12D（RMC9805）和泛KRAS（Draxonrasib）抑制剂的联合。每种联合均表现出稳健的协同作用，提示同时靶向SMARCA2和KRAS可能是一种有前景的治疗策略。此外，我们研究了SMARCA2抑制剂与NSCLC标准化疗药物的联合效应；与奥沙利铂、多西他赛或培美曲塞的联合显示出部分协同作用，表明SMARCA2抑制剂可能作为联合化疗的有前景的候选药物。总之，HD-11273与KRAS靶向治疗的联合在SMARCA4和KRAS共突变NSCLC的临床前模型中显示出协同抗肿瘤效应。此外，HD-11273与NSCLC化疗标准治疗的联合在SMARCA4突变型NSCLC的临床前模型中显著增强了抗肿瘤活性。
查看英文原文 English abstract
SMARCA2 (BRM) and SMARCA4 (BRG1) are the catalytic subunits of SWI/SNF chromatin remodeling complexes, functioning in a mutually exclusive manner to regulate nucleosome composition via their ATPase domains. Pan-cancer analysis indicates that SMARCA4 mutations occur at all cancers, in particular, SMARCA4 mutations are found in 8-10% of non-small cell lung cancer (NSCLC) cases, suggesting SMARCA2 as a potential synthetic lethal target. Several studies reported that the co-mutation frequency of KRAS and SMARCA4 in NSCLC is approximately 7.7-10%, with about 39-47% of these SMARCA4-mutant patients harboring KRAS mutations. And patients with SMARCA4-mutant NSCLC generally demonstrate poor responses to conventional chemotherapy. We selected HD-11273 as a preclinical candidate, which showed improved physicochemical properties through the preparation of a specific salt of HD-10991, a selective SMARCA2 inhibitor. Here, we report a combination study of HD-11273 with standard chemotherapy and KRAS inhibitors currently in development. HD-11273 monotherapy significantly inhibited growth of SMARCA4-del A549 CDX model as well as patient derived cancer organoid (PDO) models. Combination therapies targeting multiple pathways are considered essential for overcoming monotherapy limitations, including resistance arising from prolonged treatment. To evaluate the therapeutic benefit, we tested our selective SMARCA2 inhibitor in combination with KRASG12C (storasib, adagrasib), KRASG12D (RMC9805), and pan-KRAS (Draxonrasib) inhibitors in cancers harboring KRAS and SMARCA4 co-mutations. Each combination exhibited robust synergy, suggesting that dual targeting of SMARCA2 and KRAS could be a promising therapeutic strategy. Additionally, we investigated the combinatory effect of a SMARCA2 inhibitor with standard chemotherapy agents for NSCLC; combination with oxaliplatin, docetaxel, or pemetrexed showed partial synergy, indicating that SMARCA2 inhibitors may serve as promising candidates for combination chemotherapy. In conclusion, the combination of HD-11273 with KRAS targeted therapy showed synergistic anti-tumor effect in preclinical models of SMARCA4 and KRAS co-mutated NSCLC. Also, the combination of HD-11273 with standard care for NSCLC chemotherapy significantly enhances anti-tumor activity in preclinical models of SMARCA4-mutated NSCLC.
利益披露 Disclosure
H. Kim, None..
M. Choi, None..
J. Park, None..
G. Yang, None..
M. Park, None..
H. Choi, None..
Y. Kim, None..
D. Kim, None..
D. Kim, None..
S. Kim, None..
S. Lee, None.