Combination Therapy to Improve MAPK Pathway Inhibitor Efficacy in BRAF and KRAS M

描述（由申请人提供）：BRAF和KRAS的激活突变是MAPK通路的关键信号成分，是人类癌症中最常见的致癌突变之一，分别发生在所有癌症的7%和20%，以及结肠直肠癌（crc）的10% -15%和40%。因此，针对含有BRAF和KRAS突变的癌症的有效靶向治疗策略将具有深远的临床影响，而MAPK信号的抑制剂，包括BRAF和MEK抑制剂，目前正在临床开发中。虽然BRAF抑制剂在BRAF突变型黑色素瘤中被证明非常有效，但在BRAF突变型结直肠癌中的结果却令人失望。尽管这种差异的原因尚不完全清楚，但我们小组和其他人最近的工作发现，EGFR信号可能在耐药性中起关键作用。我们的初步研究还表明，基于BRAF抑制剂的靶向治疗组合，如BRAF/MEK联合（目前正在临床试验中）或BRAF/EGFR联合抑制，可能会提高BRAF突变型CRC的疗效。尽管KRAS是最常见的突变癌基因，但目前还没有针对KRAS突变癌症的有效治疗方法，这主要是因为KRAS蛋白本身已被证明难以用小分子直接靶向。靶向单一下游KRAS效应通路（如MEK）在临床试验中也取得了有限的成功，可能是因为KRAS激活了多个重要的信号通路。之前，我们的实验室和其他研究表明，联合靶向多种KRAS效应通路（MEK和PI3K）可以在KRAS突变小鼠肿瘤模型中引起戏剧性的反应，但初步数据表明，MEK/PI3K联合抑制可能仅对KRAS突变癌症的一部分有效，这强调了需要额外有效的抑制剂组合。该提案的总体假设是，BRAF和MEK抑制剂在BRAF和KRAS突变型CRC中的有限疗效分别涉及激活其他关键途径，这些途径降低了这些癌症对MAPK信号“成瘾”的程度，限制了这些抑制剂作为单一药物的有效性。我们的目标是为BRAF和KRAS突变型癌症开发新的联合治疗策略，特别是CRC。基于我们最近发现的EGFR介导BRAF突变型结直肠癌对BRAF抑制剂的耐药性，我们将利用体外模型和BRAF突变型结直肠癌新型靶向治疗试验的患者肿瘤活检，对EGFR在BRAF抑制剂耐药性中的作用进行全面分析。在KRAS突变型CRC中，我们将采用我们实验室开发的一种新的shRNA药物筛选方法来确定MEK抑制剂联合治疗的新靶点。新的组合将在KRAS突变型CRC的尖端小鼠模型中进行评估，目的是快速确定有效的靶向治疗组合。针对这些癌症的新治疗策略将代表个性化癌症医学的重大进步，对大量癌症患者具有显著的临床益处。

DESCRIPTION (provided by applicant): Activating mutations in BRAF and KRAS, key signaling components of the MAPK pathway, are among the most common oncogenic mutations in human cancer, occurring in ~7% and ~20% of all cancers and in ~10-15% and ~40% of colorectal cancers (CRCs), respectively. Consequently, effective targeted therapy strategies for cancers harboring BRAF and KRAS mutations would have a profound clinical impact, and inhibitors of MAPK signaling, including BRAF and MEK inhibitors, are currently in clinical development. While BRAF inhibitors proved remarkably effective in BRAF mutant melanoma, results have been disappointing in BRAF mutant CRC. Although the reason for this disparity is not fully understood, recent work from our group and others has found that EGFR signaling may play a key role in resistance. Our preliminary studies have also shown that BRAF inhibitor-based targeted therapy combinations, such as combined BRAF/MEK (currently in clinical trials) or combined BRAF/EGFR inhibition, may improve efficacy in BRAF mutant CRC. Although KRAS is the most commonly mutated oncogene, no effective therapies exist for KRAS mutant cancers, largely because the KRAS protein itself has proven difficult to target directly with small molecules. Targeting single downstream KRAS effector pathways (e.g. MEK) has also met limited success in clinical trials, likely because KRAS activates multiple important signaling pathways. Previously, our laboratory and others showed that combined targeting of more than one KRAS effector pathway (MEK and PI3K) can cause dramatic responses in KRAS mutant mouse tumor models, but preliminary data suggests that combined MEK/PI3K inhibition may only be effective in a subset of KRAS mutant cancers, underscoring the need for additional effective inhibitor combinations. The overall hypothesis of this proposal is that the limited efficacy of BRAF and MEK inhibitors in BRAF and KRAS mutant CRC, respectively, involves activation of other key pathways that reduce the extent to which these cancers are "addicted" to MAPK signaling, constraining the effectiveness of these inhibitors as single-agents. We aim to develop novel combination therapy strategies for BRAF and KRAS mutant cancers, focusing specifically on CRC. Building on our recent discovery that EGFR mediates resistance to BRAF inhibitors in BRAF mutant CRC, we will perform a comprehensive analysis of the role of EGFR in BRAF inhibitor resistance, utilizing in vitro models and patient tumor biopsies from a novel targeted therapy trial for BRAF mutant CRC. In KRAS mutant CRC, we will employ a novel pooled shRNA drug screen developed in our laboratory to identify new targets for combination therapy with MEK inhibitors. Novel combinations will be evaluated in cutting-edge mouse models of KRAS mutant CRC with the goal of rapidly identifying effective targeted therapy combinations. New therapeutic strategies for these cancers would represent a major advance in personalized cancer medicine with significant clinical benefit for a large population of cancer patients.