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BRAF V600的组成性激活。 MAPK信号通路，并赋予死亡率相对于BRAF野生型CRC增加约2倍。因此，在本发明中， 迫切需要用于这种疾病的新的有效疗法。而RAF抑制剂（RAFi），如 vemurafenib和dabrafenib在BRAF突变型黑色素瘤中非常有效（约60-80%的缓解率）， 在BRAF突变型CRC中对RAFi单一疗法的应答率仅为~ 5%。我们最初的努力是定义 在BRAF突变CRC中起作用的耐药机制导致了RAFi组合的新的临床试验。 通过实验室模型、临床试验和临床标本分析的集中整合， 在BRAF突变型CRC患者的护理方面取得了显著进展， 在过去几年中从约5%增加到约40%。尽管如此，仍有相当一部分患者对 治疗，而那些有反应的患者最终会产生耐药性。因此，进一步优化 BRAF突变型CRC迫切需要治疗。因此，我们提出了一个创新的，高度转化的 利用已建立的和患者来源的肿瘤模型进行详细信号传导研究的方法， 肿瘤患者源性肿瘤模型的全面分子评估和表征 来自入组尖端临床试验的BRAFm CRC患者的活检，以及 血浆ctDNA用于确定原发性和获得性耐药机制以及BRAFm中异质性的作用 《儿童权利公约》。我们还将评估一种新的收敛抑制策略，采用ERK抑制剂，支持我们的研究。 初步数据，作为克服阻力的潜在战略。这项拟议的工作将提供关键的见解 为未来的临床试验指导新的和更有效的治疗策略的开发。

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.