APC + TP53 Combinatorial Mutations Emerging as Biomarkers to Predict EGFRI Sensitivity

项目摘要/摘要 结直肠癌(CRC)是癌症死亡的主要原因，如果及早发现是可以治愈的。不幸的是， 许多结直肠癌在较晚期被诊断出来，治愈率仍然很低，五年内治愈率为20% 生死存亡。表皮生长因子受体(EGFR)是FDA批准的转移瘤的主要治疗靶点 可能未得到充分利用的CRC。到目前为止，仍然很难确定哪些患者可能从EGFRi治疗中受益。 事实上，唯一确定的EGFRi治疗的生物标志物是下游基因的突变，这些基因激活了 RAS途径(KRAS(40%)，NRAS(5%)，可能还有BRAF(10%))。不幸的是，这些生物标志物 在预测无应答者方面，负面预测只有~50%的准确率。因此，准确预测 EGFRi的敏感性仍然是个问题。我们最近采用了一种新的混合方法，使用预测 西妥昔单抗敏感性(CTX-S)基因在468例全局基因重合的结直肠癌中的表达特征评分 表达和外显子组测序数据以确定KRAS/BRAF/NRAS中可能存在的突变以外的突变 预测EGFRi响应者。我们发现，含有APC+TP53突变组合的肿瘤是 预计对西妥昔单抗(CTX)最敏感。而大多数结直肠癌(70%)有截断 APC突变和TP53突变存在于50%的结直肠癌中，两种基因同时突变 在~25%的结直肠癌中，到目前为止从未在临床试验中进行过严格的测量。因此，我们假设联合- 突变的APC+TP53作为一种新的复合生物标志物用于识别CTX敏感肿瘤 WT RAS/RAF患者的应答率，并有可能将治疗扩展到一些突变的KRAS患者。至 理解和验证这种新的生物标志物的全部潜力，在这里我们试图确定细胞的影响 APC和TP53突变增加了肿瘤对EGFR抑制的敏感性。此外，我们试图确定 与这些突变的存在相关的其他早期/中期反应生物标志物。最后， 我们将确定这些突变是否改变了基于基因表达的共识分子亚型(CMS)。 患有CMS2的肿瘤被预测对EGFR抑制有更高的敏感性，并且似乎与 在我们的人类数据集中有APC+TP53突变。我们试图确定APC+TP53的突变是否可以 将分子亚型CMS1、3、4转化为CMS2，与增强EGFRi敏感性一致。此应用程序 将为新的分子生物标记物提供必要的临床前验证，以最好地预测哪些结直肠癌 将对EGFRi做出响应，并支持可能导致扩展的后续未来临床验证 应用FDA批准的未充分利用的靶向治疗。

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a major cause of cancer deaths which is curable if detected early. Unfortunately, many CRC tumors are diagnosed at more advanced stages where cure rates remain low with 20% five-year survival. The epidermal growth factor receptor (EGFR) is a major FDA-approved therapeutic target in metastatic CRC that may be underutilized. To date, it is still difficult to identify patients who may benefit from EGFRi therapy. In fact, the only identified biomarkers for EGFRi therapy are mutations in downstream genes that activate the RAS pathway (KRAS (40%), NRAS (5%), and possibly BRAF (10%)). Unfortunately, these biomarkers are negative predictors that are only ~50% accurate in predicting non-responders. Thus, accurate prediction of EGFRi sensitivity is still problematic. We have recently employed a novel hybrid approach using a predictive cetuximab sensitivity (CTX-S) gene expression signature score in 468 CRC tumors with coincident global gene expression and exome sequencing data to identify mutations beyond those in KRAS/BRAF/NRAS that might predict EGFRi responders. We found that tumors harboring the combination of APC + TP53 mutations are predicted to be the most sensitive to cetuximab (CTX). Whereas most CRC tumors (70%) have truncating mutations in APC and mutations in TP53 are present in 50% of CRC tumors, co-mutation of both genes is present in ~25% of CRC and heretofore has never been rigorously measured in clinical trials. Thus, we hypothesize co- mutated APC + TP53 as a new composite biomarker to identify CTX sensitive tumors that would allow greater response rates in WT RAS/RAF patients and potentially extend therapy to some mutant KRAS patients. To understand and validate the full potential of this novel biomarker, here we seek to determine the cellular impact of the APC and TP53 mutations that increase the tumor sensitivity to EGFR inhibition. Further, we seek to identify additional early/intermediate biomarkers of response correlating with the presence of these mutations. Finally, we will determine if these mutations alter the gene expression–based consensus molecular subtype (CMS). Tumors with CMS2 are predicted to have greater sensitivity to EGFR inhibition and appear to strongly correlate with APC + TP53 mutations in our human datasets. We seek to determine if mutations in APC + TP53 can convert molecular subtypes CMS1,3,4 to CMS2, coincident with enhancing EGFRi sensitivity. This application will provide the necessary pre-clinical validation of novel molecular biomarkers to best predict which CRC tumors will be responsive to EGFRi, and to support subsequent future clinical validation that may lead to expanded application of an under-used, FDA-approved targeted therapy.