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

项目概要/摘要 结直肠癌（CRC）是癌症死亡的主要原因，如果早期发现，是可以治愈的。不幸的是， 许多CRC肿瘤在更晚期被诊断，其中治愈率仍然很低， 生存表皮生长因子受体（EGFR）是FDA批准的转移性肝癌的主要治疗靶点。 可能未充分利用的CRC。迄今为止，仍然难以确定可能从EGFRi治疗中获益的患者。 事实上，EGFRi治疗唯一确定的生物标志物是下游基因中的突变，这些突变激活了EGFR。 RAS途径（KRAS（40%）、NRAS（5%）和可能的BRAF（10%））。不幸的是，这些生物标志物 阴性预测因子在预测无应答者方面的准确率仅为~50%。准确预测 EGFRi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 468例具有一致全局基因的CRC肿瘤中的西妥昔单抗敏感性（CTX-S）基因表达特征评分 表达和外显子组测序数据，以确定KRAS/BRAF/NRAS中可能 预测EGFRi应答者。我们发现，携带APC + TP 53突变组合的肿瘤是 预测对西妥昔单抗（CTX）最敏感。而大多数CRC肿瘤（70%）具有截短性， APC突变和TP 53突变存在于50%的CRC肿瘤中，存在两种基因的共突变。 在~25%的CRC中，迄今为止从未在临床试验中严格测量。因此，我们假设共同- 突变的APC + TP 53作为新的复合生物标志物，以鉴定CTX敏感性肿瘤， WT RAS/RAF患者的缓解率，并可能将治疗扩展到一些突变型KRAS患者。到 为了了解和验证这种新型生物标志物的全部潜力，我们在这里试图确定细胞的影响， APC和TP 53突变增加了肿瘤对EGFR抑制的敏感性。此外，我们还试图确定 与这些突变的存在相关的额外的早期/中期应答生物标志物。最后， 我们将确定这些突变是否改变基于基因表达的共有分子亚型（CMS）。 预测具有CMS 2的肿瘤对EGFR抑制具有更大的敏感性，并且似乎与EGFR抑制强烈相关。 APC + TP 53突变。我们试图确定APC + TP 53中的突变是否可以 将分子亚型CMS 1、3、4转化为CMS 2，与增强EGFR i敏感性一致。本申请 将提供新的分子生物标志物的必要的临床前验证，以最好地预测哪些CRC肿瘤 将对EGFRi作出反应，并支持随后的未来临床验证， 一种未被充分利用的FDA批准的靶向治疗的应用。

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.