Dual targeting of cGAS-STING and splicing to prime lung cancer immunogenicity

项目摘要 肺癌是美国癌症相关死亡的主要原因。非小细胞肺癌 (非小细胞肺癌)是最常见的肺癌类型，尽管积极的治疗策略包括 肺癌患者的内科治疗、手术切除和放射治疗的5年生存率 仍然令人沮丧。最近，美国食品和药物管理局(FDA)批准了几个免疫检查站 以抑制剂为基础的治疗非小细胞肺癌，确立免疫疗法为有效的治疗方法 非小细胞肺癌的选择和标准护理治疗。尽管如此，许多患者对免疫没有反应。 检查点封锁(ICB)和KRAS和STK11减刑患者亚组(KL) 出现了一种对ICB耐药的特别具有侵袭性、免疫抑制的非小细胞肺癌。我们的团队已经 最近发现，通过用表观遗传去抑制剂治疗KL突变的非小细胞肺癌，一种 抗肺癌免疫反应中的关键蛋白，干扰素基因的刺激物(STING)被恢复。 当随后通过对纺锤体的脉冲抑制来提供刺痛通路的刺激时 组装检查点蛋白，单极纺锤体1(Mps1)，发生有效的抗肿瘤反应，恢复 对ICB的敏感性。虽然这些发现尚未在KL突变的非小细胞肺癌的临床样本中得到验证， 这些样本现在可以用于研究。对这一治疗策略的验证将表明它是 有可能克服KL突变引起的免疫抑制，但它不会产生新的抗原 推动持久的抗肿瘤免疫反应。幸运的是，Mps1与CDC2样蛋白有相同的激酶同源性 作为信使核糖核酸剪接的关键调节因子，激酶(CLK2)和双Mps1/CLK2抑制剂已经被开发出来。这 提供独特的机会，通过额外的潜水持久的抗肿瘤免疫反应 基因剪接的同步药理干扰。事实上，剪接的药物调节 最近被证明是一种决定性的、未被开发的方法来产生新的抗原，从而产生抗肿瘤 免疫反应。因此，这一奖学金提案的总体目标是提供高级博士后 对转化型癌症免疫治疗研究进行培训，同时评估一种新的增强 高度侵袭性和抗药性的非小细胞肺癌的免疫原性。我们将通过(1)验证来实现这一点 ICB耐药的临床标本中表遗传下调STING和脉冲MPS1抑制的作用 KL突变的非小细胞肺癌和(2)检测双重Mps1/CLK2的mRNA剪接断裂和新抗原的产生 抑制剂处理KL突变的非小细胞肺癌。这些目标将共同寻求改善治疗结果 同时加强训练有素的内科科学家队伍。

Project Summary Lung cancer is the leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and despite aggressive treatment strategies that include medical therapy, surgical resection, and radiation therapy, 5-year survival rates for patients with lung cancer remain dismal. Recently, the US Food and Drug Administration (FDA) approved several immune checkpoint inhibitor-based therapies for the treatment of NSCLC, establishing immunotherapy as an effective therapeutic option and standard-of-care treatment for NSCLC. Despite this, many patients fail to respond to immune checkpoint blockade (ICB) and the subgroup of patients with KRAS and STK11 commutations (KL) has emerged as a particularly aggressive, immunosuppressive form of NSCLC resistant to ICB. Our group has recently discovered that by treating KL-mutated NSCLC with epigenetic de-repressing agents, expression of a key protein in the immune response against lung cancer, stimulator of interferon genes (STING), is restored. When stimulus for the STING pathway is subsequently provided through pulsed inhibition of a spindle assembly checkpoint protein, monopolar spindle 1 (MPS1), potent anti-tumor responses occur, restoring sensitivity to ICB. While these findings have yet to be validated in clinical samples of KL-mutated NSCLC, these samples are now available to use for study. Validation of this therapeutic strategy will show that it is possible to overcome KL-mutation induced immunosuppression, though, it does not generate neoantigens to drive durable anti-neoplastic immune responses. Fortunately, MPS1 shares kinase homology with CDC2-like kinase (CLK2), a key regulator of mRNA splicing, and dual MPS1/CLK2 inhibitors have been developed. This provides the unique opportunity to additionally dive durable anti-tumor immune responses through simultaneous pharmacological disruption of mRNA splicing. Indeed, pharmacological modulation of splicing was recently demonstrated as a definitive, untapped method to generate neoantigens that elicit anti-tumor immune responses. The overall goal of this fellowship proposal is, therefore, to provide advanced post-doctoral training in translational cancer immunotherapy research while evaluating a novel approach to enhance immunogenicity in a highly aggressive and resistant form of NSCLC. We will accomplish this by (1) validating the effect of epigenetic de-repression of STING and pulsed MPS1 inhibition in clinical samples of ICB-resistant, KL-mutated NSCLC and (2) examining mRNA splice disruption and neoantigen generation in dual MPS1/CLK2 inhibitor treated KL-mutated NSCLC. Together these aims will seek to improve therapeutic outcomes for patients with NSCLC while enhancing the pool of highly trained physician-scientists.