Targeting SMARCA2 as a therapeutic strategy in SMARCA4 mutant lung cancer

靶向 SMARCA2 作为 SMARCA4 突变肺癌的治疗策略

• 批准号: 10684259
• 负责人: Yonathan Lissanu
• 金额: $ 52.69万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684259
• 关键词: ARID1A gene; Ablation; Biological; Biological Models; Biology; CRISPR/Cas technology; Cancer Biology; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Cells; Chemicals; Chromatin; Chromatin Remodeling Factor; Complex; Data; Development; Disease; Epidermal Growth Factor Receptor; Epigenetic Process; Foundations; Frequencies; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Genomics; Goals; Growth; Heterozygote; Immunotherapy; In Vitro; Knowledge; Lead; Malignant neoplasm of lung; Mediating; Mus; Mutate; Mutation; Names; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Pharmacodynamics; Positioning Attribute; Protac; Proteins; Reporting; Resistance; Role; SMARCA2 gene; SMARCA4 gene; Sucrose; Technology; Therapeutic; Therapeutic Index; Validation; Xenograft Model; Xenograft procedure; analog; cancer cell; cancer subtypes; clinical development; clinical translation; drug mechanism; efficacy testing; experimental study; genetic approach; improved; in vivo; inhibitor; insight; interest; loss of function; lung cancer cell; mortality; mutant; novel; novel therapeutics; patient derived xenograft model; pre-clinical; preclinical development; programmed cell death ligand 1; resistance mechanism; small molecule; targeted treatment; therapeutic target; therapeutically effective; tumor; tumor growth

Project Summary Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports and our own data have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4. However, identifying selective inhibitors of SMARCA2 has been challenging. Hence, we have developed novel SMARCA2 degrading small molecules based on the proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. We further showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells. Mechanistically, we showed that YD23 induces changes in chromatin accessibility only in SMARCA4 deficient cells. Taking these observations together, we hypothesize that SMARCA2 degradation using YD23 is an attractive therapeutic strategy with promising therapeutic index in lung cancers with inactivating mutations in SMARCA4. The major objective of the proposed study is to provide preclinical evidence to guide future development of YD23 (or its analogs) in patients with SMARCA4 mutant lung cancer. While we have shown marked sensitivity of SMARCA4 mutant lung cancer cell lines to YD23, we still do not know the detailed mechanistic basis for this activity. Hence, we intend to perform gene expression, epigenetic and chromatin accessibility studies followed by integrative analysis to triangulate on direct target genes whose chromatin landscape is altered by presence or absence of SMARCA2 in SMARCA4 mutant cancer cells. While our in vitro cancer cell growth inhibitory studies are encouraging, a systematic exploration in vivo using various orthogonal model systems is required to aid the preclinical development of SMARCA2 degraders. Thus, we propose to determine the potential of YD23 mediated SMARCA2 degradation in SMARCA4 mutant xenograft and patient derived xenograft (PDX) model systems. Due to the unique microenvironment of lung cancer we will also test efficacy of YD23 in GEM models of lung cancer. Finally, SMARCA2 as a synthetic lethal partner of SMARCA4 has so far been described by in vitro experiments. In vivo genetic validation is critical to unequivocally demonstrate the requirement of a gene of interest in the development of a genetically defined subtype of cancer. Thus, we aim to perform CRISPR-Cas9 mediated Smarca2 genetic ablation to determine the extent of its involvement in the development and biology of Smarca4 mutant GEM models. In conclusion, our study is expected to provide mechanistic insight into the synthetic lethal genetic relationship between SMARCA2 and SMARCA4 and lay the foundation for future clinical development of SMARCA2 degraders as therapeutics.

项目摘要 肺癌是癌症死亡的首要原因。尽管最近的进展，大多数患者 肺癌缺乏有效的治疗选择，强调迫切需要额外的治疗方法。 基因组学研究已经确定了SWI/SNF染色质重塑复合物亚基的频繁突变 包括SMARCA 4和ARID 1A在非小细胞肺癌中的发生率高达33%， 这种疾病使其成为肺癌中最常见的突变复合物。最近的报告和我们自己的数据显示， 鉴定出paraerobic SMARCA 2对SMARCA 4是合成致死的。然而，识别选择性抑制剂 SMARCA 2是一个挑战。因此，我们开发了新型SMARCA 2降解小分子， 基于蛋白水解靶向嵌合体（PROTAC）技术。我们证明，YD 23，我们的领导者， SMARCA 2 PROTAC，强效且选择性诱导SMARCA 2降解。我们进一步证明YD 23 选择性抑制SMARCA 4突变型肺癌细胞的生长。从机制上讲，我们表明YD 23诱导 仅在SMARCA 4缺陷细胞中染色质可及性的变化。 将这些观察结果结合在一起，我们假设使用YD 23的SMARCA 2降解是 在具有失活突变的肺癌中具有有吸引力的治疗策略和有前景的治疗指数， SMARCA 4.这项研究的主要目的是提供临床前证据，以指导未来的研究。 在SMARCA 4突变型肺癌患者中，YD 23（或其类似物）的发展。虽然我们已经表明 SMARCA 4突变肺癌细胞系对YD 23的敏感性显著，我们仍然不知道详细的 这一活动的基础。因此，我们打算进行基因表达，表观遗传和染色质 可及性研究，然后进行综合分析，以三角测量直接靶基因，其染色质 在SMARCA 4突变癌细胞中，SMARCA 2的存在或不存在改变了景观。我们的试管婴儿 癌细胞生长抑制研究是令人鼓舞的，一个系统的探索，在体内使用各种正交 需要模型系统来帮助SMARCA 2降解剂的临床前开发。因此，我们建议 确定SMARCA 4突变异种移植物和患者中YD 23介导的SMARCA 2降解的潜力 衍生的异种移植物（PDX）模型系统。由于肺癌独特的微环境，我们还将测试 YD 23在肺癌GEM模型中的功效。最后，SMARCA 2作为SMARCA 4的合成致死伴侣， 迄今为止都是通过体外实验描述的。体内基因验证对于明确 证明在遗传上确定的癌症亚型的发展中需要感兴趣的基因。 因此，我们的目标是进行CRISPR-Cas9介导的Smarca 2基因消融，以确定其在基因治疗中的作用程度。 参与Smarca 4突变GEM模型的开发和生物学。总之，我们的研究是 预计将提供对SMARCA 2和SMARCA 3之间的合成致死遗传关系的机制性见解。 SMARCA 4，并为SMARCA 2降解剂作为治疗药物的未来临床开发奠定基础。