Paradoxical Effects of SETD2 Inactivation in EGFR- and KRAS-driven Lung Adenocarcinoma

SETD2 失活对 EGFR 和 KRAS 驱动的肺腺癌的矛盾效应

基本信息

批准号：
10677503
负责人：
Katherine Doerig
金额：
$ 4.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677503
关键词：
Acceleration BRAF gene Benchmarking Cancer Etiology Cell Death Cell Line Cell Proliferation Conflict (Psychology)Data Development Disease Epidermal Growth Factor Receptor FRAP1 gene Genes Genetic Genetic Epistasis Genotype Growth Human Individual KRAS oncogenesis KRAS2 gene Laboratories Lung Adenocarcinoma MAP Kinase Gene Maintenance Malignant Neoplasms Modeling Mus Mutate Mutation Oncogenes Oncogenic PIK3CG gene Pathway interactions Patients Pattern Protein Biosynthesis Proto-Oncogene Proteins c-akt Role STK11 gene Signal Transduction Testing Therapeutic Intervention Therapeutically Targetable Tumor Burden Tumor Cell Line Tumor Promotion Tumor Suppressor Proteins Tumor-Derived Work antagonist cancer cell cancer genome cancer therapy cancer type driver mutation fitness genome sequencing histone methyltransferase improved insight mouse model neoplastic cell new therapeutic target outcome disparities prevent synergism tumor tumor growth tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY Mutual exclusivity and co-occurrence of cancer causing mutations are due to pairwise genetic relationships that include oncogenic redundancy and synthetic lethality. These interactions suggest that the cancer-promoting effects of one mutation are dependent on the presence of another, a contingency that can be exploited in the development of new cancer therapies. Certain mutations have contrasting effects, promoting cancer in one mutational context but limiting it in another. SETD2 inactivation in lung adenocarcinoma occurs in 9% of tumors overall, and frequently co-occurs with oncogenic KRAS, but is mutually exclusive with oncogenic EGFR, the most frequent driver genes of this disease. Our lab was the first to identify SETD2 as a potent tumor suppressor in a KRAS-driven mouse model. However, paradoxically, Setd2 inactivation prevents tumor growth in the context of oncogenic EGFR, suggesting an antagonism between these alterations. The opposing effects of Setd2 inactivation are surprising given that KRAS is directly downstream of EGFR and activates the MAPK pathway, a driver of many cancer types. Given that KRAS and EGFR share this major tumorigenic pathway, I hypothesize that Setd2 inactivation is specifically synergistic with activation of the MAPK pathway, but incompatible with a separate pathway that is also downstream of EGFR. An important clue in deciphering this incompatibility is the epistatic relationship between SETD2 and LKB1, another frequently inactivated gene. Although both genes are powerful tumor suppressors in KRAS- driven models, co-mutation conferred no additional growth advantage, indicating that these genes act in the same pathway. Additionally, Lkb1 inactivation has the same paradoxical antagonism in EGFR-driven tumors. Inactivation of Lkb1 results in constitutively activated mTORC1 signaling which is a common feature of many cancers. My preliminary data demonstrate that Setd2 inactivation also promotes mTORC1 activity in KRAS- driven tumors. Likewise, oncogenic EGFR directs mTORC1 signaling via the PI3K-AKT axis and is reliant on this pathway for tumor maintenance, while oncogenic KRAS is not. Given the stimulation of mTORC1 signaling by Setd2 and its synthetic lethality with oncogenic EGFR which also activates mTOR, I hypothesize that the heightened mTORC1 activity present in Setd2-inactivated tumors is incompatible with oncogenic EGFR. To test these hypotheses, I first aim to determine whether Setd2 inactivation is synergistic with oncogenic MAPK signaling using a BRAF-driven mouse model. Second, I will determine whether excess mTORC1 signaling is responsible for EGFR-SETD2 antagonism by modulating this pathway in each driver context using tumor cell lines. This study will begin to characterize the synthetic lethal relationship between two frequently mutated genes in lung adenocarcinoma. Understanding these interactions will enable development of new therapies that target genotype specific vulnerabilities.

项目概要致癌突变的相互排他性和共现性是由于成对遗传所致关系包括致癌冗余和合成致死率。这些相互作用表明一种突变的促癌作用取决于另一种突变的存在，这是一种可能发生的意外情况被用于开发新的癌症疗法。某些突变具有相反的效果，促进癌症在一种突变背景下发生，但在另一种突变背景下受到限制。肺腺癌中发生 SETD2 失活总体而言，存在于 9% 的肿瘤中，并且经常与致癌 KRAS 共同发生，但与致癌 EGFR，该疾病最常见的驱动基因。我们的实验室是第一个将 SETD2 识别为 KRAS 驱动的小鼠模型中的有效肿瘤抑制剂。然而，矛盾的是，Setd2 失活会阻止肿瘤生长在致癌 EGFR 的背景下，表明这些改变之间存在拮抗作用。这鉴于 KRAS 直接位于 EGFR 下游，Setd2 失活的相反作用令人惊讶激活 MAPK 通路，这是许多癌症类型的驱动因素。鉴于 KRAS 和 EGFR 共享这个专业致瘤途径，我假设 Setd2 失活与 MAPK 通路，但与 EGFR 下游的单独通路不兼容。破译这种不兼容性的一个重要线索是 SETD2 和 LKB1，另一个经常失活的基因。尽管这两个基因在 KRAS 中都是强大的肿瘤抑制因子驱动模型中，共突变没有带来额外的生长优势，表明这些基因在相同的途径。此外，Lkb1 失活在 EGFR 驱动的肿瘤中具有相同的矛盾拮抗作用。 Lkb1 失活会导致 mTORC1 信号传导持续激活，这是许多细胞的共同特征癌症。我的初步数据表明 Setd2 失活也会促进 KRAS 中 mTORC1 的活性驱动的肿瘤。同样，致癌 EGFR 通过 PI3K-AKT 轴指导 mTORC1 信号传导，并且依赖于该途径用于肿瘤维持，而致癌 KRAS 则不然。考虑到 mTORC1 信号传导的刺激通过 Setd2 及其与致癌 EGFR 的合成致死性，EGFR 也激活 mTOR，我假设 Setd2 失活肿瘤中 mTORC1 活性增强，与致癌 EGFR 不相容。到为了检验这些假设，我首先旨在确定 Setd2 失活是否与致癌 MAPK 具有协同作用使用 BRAF 驱动的小鼠模型进行信号传导。其次，我将确定是否存在过量的 mTORC1 信号传导通过使用肿瘤细胞在每个驱动环境中调节该通路来负责 EGFR-SETD2 拮抗作用线。这项研究将开始描述两个经常突变的基因之间的综合致死关系肺腺癌中的基因。了解这些相互作用将有助于开发新疗法针对基因型特定的漏洞。