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

APC TP53 组合突变作为预测 EGFRI 敏感性的生物标志物

• 批准号: 10610600
• 负责人: TIMOTHY J YEATMAN
• 金额: $ 17.12万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10610600
• 关键词: APC mutation; Affect; Annexins; Apoptosis; BRAF gene; Biological Assay; Biological Markers; Cancer Etiology; Categories; Cell Line; Cell Survival; Cellular Assay; Cessation of life; Cetuximab; Clinical; Clinical Trials; Colorectal Cancer; Complex; Consensus; DNA sequencing; Data; Data Set; Databases; Development; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exploratory/Developmental Grant; FDA approved; Feedback; Future; Gene Expression; Gene Expression Profile; Genes; Human; Hybrids; KRAS2 gene; Lead; Ligands; MEKs; Measures; Modeling; Mutate; Mutation; Organoids; Pathway interactions; Patients; Pharmaceutical Preparations; Proto-Oncogene Proteins c-akt; Ras/Raf; Receptor Inhibition; Receptor Signaling; Role; Secondary to; Signal Pathway; TP53 gene; Therapeutic; Validation; base; bevacizumab; cell growth; chemotherapy; clinical investigation; colon cancer cell line; colon cancer patients; combinatorial; drug sensitivity; drug-sensitive; exome sequencing; inhibitor therapy; metastatic colorectal; molecular marker; molecular subtypes; mutant; mutational status; novel; novel marker; panitumumab; phospholipase C gamma; pre-clinical; predicting response; response; response biomarker; targeted treatment; therapeutic target; transcriptome; treatment response; tumor; tumor diagnosis

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.

项目概要/摘要 结直肠癌（CRC）是癌症死亡的主要原因，不幸的是，如果早期发现，它是可以治愈的。 许多 CRC 肿瘤在诊断时已处于晚期，五年治愈率仍然很低，仅为 20% 表皮生长因子受体 (EGFR) 是 FDA 批准的转移性治疗的主要治疗靶点。 可能未得到充分利用的 CRC 迄今为止，仍然很难确定可能从 EGFRi 治疗中受益的患者。 事实上，EGFRi 治疗唯一确定的生物标志物是激活下游基因的突变。 RAS 途径（KRAS（40%）、NRAS（5%），可能还有 BRAF（10%））不幸的是，这些生物标志物是。 阴性预测因子在预测无响应者方面的准确度仅为 50%。 EGFRi 敏感性仍然存在问题，我们最近采用了一种使用预测的新型混合方法。 468 个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，以识别 KRAS/BRAF/NRAS 之外的突变，这些突变可能 我们发现携带 APC + TP53 突变组合的肿瘤是预测 EGFRi 反应者。 预计对西妥昔单抗 (CTX) 最敏感，但大多数 CRC 肿瘤 (70%) 具有截短。 50% 的 CRC 肿瘤中存在 APC 突变和 TP53 突变，两种基因均存在共突变 大约 25% 的 CRC 中存在这种情况，迄今为止从未在临床试验中进行过严格测量。 突变的 APC + TP53 作为新的生物标志物复合物，用于识别 CTX 敏感肿瘤，这将允许更大的 WT RAS/RAF 患者的缓解率，并有可能将治疗扩展到一些突变型 KRAS 患者。 了解并验证这种新型生物标志物的全部潜力，我们在此寻求确定细胞影响 进一步，我们试图确定增加肿瘤对 EGFR 抑制敏感性的 APC 和 TP53 突变。 与这些突变的存在相关的其他早期/中期反应生物标志物。 我们将确定这些突变是否会改变基于基因表达的共有分子亚型（CMS）。 预计具有 CMS2 的肿瘤对 EGFR 抑制具有更高的敏感性，并且似乎与 我们试图确定 APC + TP53 突变是否可以影响人类数据集。 将分子亚型 CMS1、3、4 转换为 CMS2，与增强 EGFRi 敏感性一致。 将为新型生物标志物分子提供必要的临床前验证，以最好地预测哪些结直肠癌肿瘤 将响应 EGFr，并支持随后的未来临床验证，这可能会导致扩大 应用未充分利用的 FDA 批准的靶向治疗。

项目成果

An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.

综合基因表达特征分析确定了对 MEK 和 SRC 联合靶向治疗敏感的 CMS4 KRAS 突变结直肠癌。

• 发表时间: 2022-03-10
• 影响因子: 3.8
• 作者: Yang, Mingli;Davis, Thomas B;Pflieger, Lance;Nebozhyn, Michael V;Loboda, Andrey;Wang, Heiman;Schell, Michael J;Thota, Ramya;Pledger, W Jack;Yeatman, Timothy J
• 通讯作者: Yeatman, Timothy J

Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer.

Ras 通路激活和 MEKi 抗性评分可预测 MEKi 和 SRCi 组​​合诱导结直肠癌细胞凋亡的效率。

• 发表时间: 2022-03-11
• 影响因子: 5.2
• 作者: Davis, Thomas Benjamin;Gupta, Shilpa;Yang, Mingli;Pflieger, Lance;Rajan, Malini;Wang, Heiman;Thota, Ramya;Yeatman, Timothy J;Pledger, Warren Jackson
• 通讯作者: Pledger, Warren Jackson