Therapeutic resistance and tumor heterogeneity in BRAF mutant colorectal cancer

项目摘要 BRAF V600突变发生在约10%的结直肠癌(CRC)中，导致结构性激活 MAPK信号通路，与BRAF野生型结直肠癌相比，死亡率增加~2倍。因此， 迫切需要针对这种疾病的新的有效疗法。而RAF抑制剂(RAF)，如 维莫拉非尼和达普拉非尼对BRAF突变黑色素瘤非常有效(~60%-80%的有效率)， BRAF突变型结直肠癌对RAFI单药治疗的有效率仅为~5%。我们最初的努力是定义 在BRAF突变的CRC中起作用的耐药机制已经导致了RAFI组合的新的临床试验。 通过这种实验室模型、临床试验和临床标本分析的重点整合， 在治疗BRAF突变的结直肠癌患者方面取得了重大进展，应答率 在过去的几年里，从~5%增加到~40%。尽管如此，仍有相当比例的患者对 治疗，那些确实有反应的患者最终会产生抵抗力。相应地，进一步优化 BRAF突变型结直肠癌亟需治疗。因此，我们提出了一种创新的、高度翻译的 利用已建立的和患者衍生的肿瘤模型进行详细的信号研究的方法， 肿瘤患者来源肿瘤模型的综合分子评估和表征 参加尖端临床试验的BRAFm结直肠癌患者的活检组织，以及连续液体活检分析 血浆ctDNA确定原发和获得性耐药机制以及异质性在BRAFm中的作用 CRC。我们还将评估一种使用ERK抑制剂的新收敛抑制策略，该策略由我们的 初步数据，作为克服阻力的潜在策略。这项拟议的工作将提供关键的见解 以指导开发新的和更有效的治疗策略，为未来的临床试验。

Project Summary BRAF V600 mutations occur in ~10% of colorectal cancers (CRCs), leading to constitutive activation of the MAPK signaling pathway, and confer a ~2-fold increase in mortality relative to BRAF wildtype CRC. Thus, novel effective therapies for this disease are critically needed. While RAF inhibitors (RAFi), such as vemurafenib and dabrafenib, are highly effective in BRAF mutant melanoma (~60-80% response rate), the response rate to RAFi monotherapy in BRAF mutant CRC is only ~5%. Our initial efforts to define the resistance mechanisms operant in BRAF mutant CRC have led to novel clinical trials of RAFi combinations. Through this focused integration of laboratory models, clinical trials, and analysis of clinical specimens, significant advances in the care of BRAF mutant CRC patients have been achieved, with response rates increasing from ~5% to ~40% in the last few years. Still, a substantial percent of patients fail to respond to therapy, and those patients that do respond eventually develop resistance. Accordingly, further optimization of therapy is critically needed for BRAF mutant CRC. Therefore, we propose an innovative, highly translational approach leveraging detailed signaling studies utilizing established and patient-derived tumor models, comprehensive molecular assessment and characterization of patient-derived tumor models from tumor biopsies from BRAFm CRC patients enrolled in cutting-edge clinical trials, and serial liquid biopsy analysis of plasma ctDNA to define primary and acquired resistance mechanisms and the role of heterogeneity in BRAFm CRC. We will also evaluate a novel convergent inhibition strategy employing ERK inhibitors, supported by our preliminary data, as a potential strategy to overcome resistance. This proposed work will provide key insights to guide development of novel and more effective therapeutic strategies for future clinical trials.