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Selectively targeting apoptosis in PIK3CA mutant colorectal cancers

选择性靶向 PIK3CA 突变结直肠癌的细胞凋亡

基本信息

批准号：
9981691
负责人：
Kris C. Wood
金额：
$ 35.71万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-12 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981691
关键词：
1-Phosphatidylinositol 3-Kinase AKT inhibition Animal Model Apoptosis Apoptotic Architecture BCL1 Oncogene BCL2 gene BCL2L11 gene BIM Bcl-2-binding protein BRAF gene CRISPR/Cas technology Cancer Etiology Cells Cessation of life Chronic Clinical Clinical Management Clinical Research Colorectal Cancer Combined Modality Therapy Development Disease Progression Dose Drug Combinations Drug Screening Extracellular Signal Regulated Kinases FBXW7 gene FOXO3A gene Foundations Generations Genes Genetic Transcription Growth Human KRAS2 gene Lead MADH4 gene Mediating Molecular Mutate Mutation Nature PIK3CA gene Pathway interactions Patients Pharmacology Phosphorylation Protein Family Proto-Oncogene Proteins c-akt Regulation Research Design Resistance Sampling Series Signal Pathway Signal Transduction Sum TP53 gene Therapeutic Toxic effect Treatment Efficacy Tyrosine Kinase Inhibitor Work Xenograft Model Xenograft procedure base bcl-xlong protein cancer diagnosis cell killing chemotherapy colon cancer cell line colon cancer patients combinatorial design disorder subtype driver mutation human data improved outcome inhibitor/antagonist loss of function member mutant mutational status phosphoproteomics preclinical study pro-apoptotic protein screening small molecule src-Family Kinases standard of care targeted treatment therapy resistant treatment response tumor

项目摘要

Project Summary Approximately 20% of colorectal cancers (CRCs), representing 25,000 patients in the U.S. each year, harbor activating driver mutations in the PIK3CA gene, which encodes the catalytic alpha subunit of phosphatidylinositol-3-kinase (PI3K). These patients have particularly poor prognoses when treated with standard-of-care chemotherapies and also fail to respond to single agent inhibitors of the PI3K pathway, a problem that underscores the compelling need for more effective therapeutic strategies for PIK3CA mutant CRC. Recently, by combining phosphoproteomic data from human CRC patients with combinatorial drug screening in CRC cell lines, we discovered that inhibitors of the extracellular signal-regulated kinase (ERK) pathway selectively sensitize PIK3CA mutant CRCs to inhibitors of the tyrosine kinase SRC without regard to the mutational status of other commonly mutated genes, including KRAS and BRAF. Through mechanistic studies, it was revealed that the selectivity of this combination for PIK3CA mutant CRCs owes to (1) SRC's selective activation only in PIK3CA mutant cells, where its pharmacological inhibition cooperates with ERK pathway inhibition to trigger apoptosis through the induction of the pro-apoptotic protein BIM, and (2) the fact that PIK3CA mutant CRCs are “addicted” to chronic BIM suppression driven by constitutive PI3K activation, and are thus vastly more sensitive to BIM induction than their PIK3CA wild-type counterparts. Acquired resistance to combinations of SRC and ERK pathway inhibitors converges on the activation of the anti- apoptotic protein BCL-XL, which directly antagonizes BIM. Upfront inhibition of BCL-XL in combination with SRC and ERK pathway inhibition leads to penetrant cell killing while blocking the emergence of acquired resistance. In this proposal, we build on these findings through a series of integrated studies examining (1) the molecular mechanisms governing SRC activation and its cooperation with the ERK pathway in PIK3CA mutant CRC; (2) the translational potential of combined SRC plus ERK pathway inhibition using studies in patient- derived xenograft (PDX) models alongside correlative clinical studies in human patient tumors; and (3) the ability of BCL-XL inhibition to reverse or block acquired resistance, alongside studies to elucidate the molecular mechanisms governing BCL-XL activation in the resistant state. The work will define an essential survival signaling network in PIK3CA mutant CRC and is expected to lead to the first selective targeted therapeutic strategies for this aggressive disease subtype.

项目概要美国每年有 25,000 名患者，约 20% 的结直肠癌 (CRC) 患有结直肠癌激活 PIK3CA 基因中的驱动突变，该基因编码催化 α 亚基磷脂酰肌醇-3-激酶 (PI3K)。这些患者在接受治疗时预后特别差标准护理化疗也无法对 PI3K 通路的单药抑制剂产生反应，这个问题强调了对 PIK3CA 突变体更有效的治疗策略的迫切需要 CRC。最近，通过将人类结直肠癌患者的磷酸化蛋白质组数据与组合药物相结合通过对 CRC 细胞系的筛选，我们发现细胞外信号调节激酶 (ERK) 的抑制剂途径选择性地使 PIK3CA 突变 CRC 对酪氨酸激酶 SRC 抑制剂敏感，而不考虑其他常见突变基因的突变状态，包括 KRAS 和 BRAF。通过机械研究表明，该组合对 PIK3CA 突变 CRC 的选择性归因于 (1) SRC 仅在 PIK3CA 突变细胞中选择性激活，其药理学抑制作用与 ERK 协同作用通过诱导促凋亡蛋白 BIM 抑制途径来触发细胞凋亡，以及 (2) 这一事实 PIK3CA 突变 CRC 对由 PI3K 激活驱动的慢性 BIM 抑制“上瘾”，因此，与 PIK3CA 野生型对应物相比，它们对 BIM 诱导更加敏感。获得的对 SRC 和 ERK 通路抑制剂组合的耐药性集中在抗-SRC 和 ERK 通路抑制剂的激活上。凋亡蛋白BCL-XL，直接拮抗BIM。 BCL-XL 的前期抑制与 SRC 和 ERK 通路抑制导致渗透性细胞杀伤，同时阻止获得性细胞的出现反抗。在本提案中，我们在这些发现的基础上通过一系列综合研究检验（1） PIK3CA突变体中控制SRC激活及其与ERK通路合作的分子机制 CRC； (2) 通过对患者的研究，结合 SRC 和 ERK 通路抑制的转化潜力衍生异种移植（PDX）模型以及人类患者肿瘤的相关临床研究；和（3） BCL-XL 抑制逆转或阻止获得性耐药的能力，以及阐明分子机制的研究在耐药状态下控制 BCL-XL 激活的机制。这项工作将定义一种基本的生存方式 PIK3CA 突变型 CRC 中的信号网络，预计将导致第一个选择性靶向治疗针对这种侵袭性疾病亚型的策略。