Mechanisms of action and therapeutic targeting of the CARM1-NFIB axis in small cell lung cancer

摘要 30年来，小细胞肺癌(SCLC)患者的治疗方案基本保持不变， 20年来没有FDA批准的新疗法，也没有靶向疗法。我们最近上演了一部电影 寻找名为CARM1的精氨酸甲基转移酶的靶标，并鉴定了NFI转录因子家族 作为本次PRMT的底物。重要的是，NFIB同时具有致癌和转移促进活性 SCLC发展的背景。我们证实了CARM1是NFIB的转录辅助激活因子。 基于这些发现，我们假设NFIB的CARM1甲基化对其促肿瘤起关键作用 功能。为了进一步支持这一前提，我们产生了一只NFIB敲门小鼠，它含有R-to-K CARM1甲基化位点突变。当这只小鼠被杂交到SCLC基因工程小鼠上时 这些小鼠的预期寿命延长了三分之一(从200天延长到300天)，这几乎是 与同一GEMM中Carm1-Lost的影响相同。这些发现增加了以小细胞肺癌为目标的可能性 使用CARM1小分子抑制剂。我们还鉴定了CARM1的效应分子(TRIM29) NFIB上的甲基化位点。在这项建议中，我们计划：(1)对这一新的 发现了CARM1/NFIB/TRIM29信号轴，以及(2)研究了靶向该信号轴的治疗潜力 Axis使用了一组临床前的小鼠模型。

ABSTRACT Treatment options for small cell lung cancer (SCLC) patients have remained largely unchanged for 3 decades, with no new FDA-approved treatments for 20 years, and no targeted therapies. We recently performed a screen for targets of an arginine methyltransferase called CARM1 and identified the NFI family of transcription factors as substrates for this PRMT. Importantly, NFIB harbors both oncogenic and metastatic promoting activities in the context of SCLC development. We confirmed that CARM1 functions as a transcriptional coactivator for NFIB. Based on these finding, we hypothesize that CARM1 methylation of NFIB is critical for its tumor-promoting functions. To further support this premise, we have generated a Nfib knockin mouse that harbors a R-to-K mutation in the CARM1 methylation site. When this mouse is crossed onto a SCLC genetically engineered mouse model (GEMM) the life expectancy of these mice is lengthened by a third (from 200 to 300 days), which is almost identical to the impact of Carm1-loss in the same GEMM. These finding raise the possibility of targeting SCLC with CARM1 small molecule inhibitors. We have also identified an effector molecule (TRIM29) for the CARM1 methylation site on NFIB. In this proposal we plan to: (1) perform a deep mechanistic analysis of this newly discovered CARM1/NFIB/TRIM29 signaling axis, and (2) investigate the therapeutic potential of targeting this axis using a battery of pre-clinical mouse models.