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

项目总结 致癌突变的相互排他性和共生性是由成对遗传引起的 包括致癌冗余和合成致命性的关系。这些相互作用表明， 一种突变的促癌作用依赖于另一种突变的存在，这种偶然性可能是 在开发新的癌症疗法方面被利用。某些突变有不同的效果，促进 癌症在一种突变的背景下，但在另一种背景下限制它。肺腺癌中发生SETD2失活 在9%的肿瘤中，并经常与致癌的KRAS共同出现，但与 致癌的EGFR，是这种疾病最常见的驱动基因。我们的实验室是第一个将SETD2鉴定为 KRAS驱动的小鼠模型中的有效肿瘤抑制因子。然而，矛盾的是，SETD2的失活阻止了 在致癌的EGFR背景下的肿瘤生长，表明这些变化之间存在拮抗作用。这个 SETD2失活的相反影响是令人惊讶的，因为KRAS直接位于EGFR和 激活MAPK通路，这是许多癌症类型的驱动因素。鉴于KRAS和EGFR共享这一主要 致癌途径，我假设SETD2的失活与SETD2的激活具有特异性的协同作用 MAPK途径，但与EGFR下游的另一条途径不兼容。 破译这种不亲和性的一个重要线索是SETD2和SETD2之间的上位关系 LKB1，另一个经常失活的基因。虽然这两个基因在KRAS中都是强大的肿瘤抑制基因- 驱动模型，共突变不会带来额外的生长优势，表明这些基因在 同一条路。此外，Lkb1失活在EGFR驱动的肿瘤中也具有同样的矛盾拮抗作用。 Lkb1的失活会导致mTORC1信号的结构性激活，这是许多 癌症。我的初步数据显示，SETD2失活也促进了KRAS中mTORC1的活性- 驱使肿瘤。同样，致癌的EGFR通过PI3K-AKT轴引导mTORC1信号，并依赖于 这是肿瘤维持的途径，而致癌的KRAS不是。给定mTORC1信号的刺激 通过SETD2及其与致癌的EGFR的合成致命性，我假设 在SETD2失活的肿瘤中，mTORC1活性升高与致癌的EGFR不相容。至 检验这些假设，我首先的目标是确定SETD2失活是否与致癌MAPK协同作用 使用BRAF驱动的小鼠模型发出信号。其次，我将确定过量的mTORC1信令是否 负责EGFR-SETD2拮抗，通过使用肿瘤细胞在每个驱动器环境中调节这一途径 台词。这项研究将开始描述两个频繁突变的人之间的合成致死关系 肺腺癌中的基因。了解这些相互作用将使新疗法的开发成为可能 它针对的是特定于基因的脆弱性。

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.