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Modulation of Mcl-1 for Treatment of Lung Cancer

调节 Mcl-1 治疗肺癌

基本信息

批准号：
10612924
负责人：
Xingming Deng
金额：
$ 42.52万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612924
关键词：
Animal Cancer Model Antineoplastic Agents Apoptotic Attenuated BRCA mutations Biological Cancer Etiology Cancer Model Cancer cell line Clinical Combined Modality Therapy DNA Double Strand Break DNA Repair DNA Repair Pathway DNA Sequence Alteration DNA biosynthesis Data Development Down-Regulation FDA approved Family member Genetic Engineering Goals Growth Human Immunotherapy In Vitro KRAS2 gene Link MAPK3 gene MCL1 gene MEKs Malignant Neoplasms Malignant neoplasm of lung Mediating Mutation Non-Small-Cell Lung Carcinoma Oncogenic Outcome PD-1 blockade PD-1 inhibitors PI3K/AKT Pathway interactions Patients Phosphorylation Phosphorylation Site Play Poly(ADP-ribose) Polymerase Inhibitor Prognosis Prognostic Marker Proteins Reporting Resistance Resistance development Role STK11 gene Signal Transduction Subgroup TP53 gene Therapeutic Therapeutic Intervention Tumor Tissue Up-Regulation Xenograft procedure anti-PD-1/PD-L1 anti-PD-L1 anti-PD-L1 therapy anti-cancer cancer cell cancer therapy homologous recombination improved in vivo inhibitor lung cancer cell mortality mutant new therapeutic target novel objective response rate overexpression patient subsets potency testing programmed cell death ligand 1 radioresistant refractory cancer replication stress small molecule survival outcome synergism targeted treatment therapeutic target therapy resistant tumor tumor growth

项目摘要

Summary KRAS mutations activate Raf/MEK/ERK1/2 that can directly phosphorylate Mcl-1 at T163, enhancing Mcl-1’s function. KRAS mutations also activate PI3K/AKT that can inactivate GSK-3 and inhibit GSK-3-mediated pMcl-1 at S159 to reduce Mcl-1 degradation. We hypothesize that KRAS mutation-activated ERK1/2 and PI3K/AKT pathways contribute to stabilization of Mcl-1 via upregulation of pMcl-1 at T163 and downregulation of pMcl-1 at S159 in lung cancer. Our preliminary data show increased pMcl-1 at T163 in tumor tissues from NSCLC patients, which associated with worse survival outcome, suggesting that pMcl-1 at T163 may provide a new therapeutic target and a prognostic biomarker in NSCLC patients. We found that Mcl-1, in addition to its canonical antiapoptotic function, plays a critical role in supporting homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs). Based on this novel function, we discovered an entirely new class of small molecule Mcl-1 inhibitor, MI-223, that interacts with the BH1 pocket of Mcl-1 and inhibits HR activity. MI-223 has potent anti-tumor activity against lung cancer in vitro and in vivo. Olaparib is an FDA-approved PARP-1 inhibitor with anti-cancer efficacy; however, only patients with HR deficiency (e.g. BRCA1/2 mutations) respond to olaparib therapy. Since MI-223 inhibits HR-mediated DNA repair, this provides a rationale for combining MI-223 and olaparib to treat various cancers, including those without BRCA1/2 mutations. Combined treatment with MI-223 and olaparib synergistically suppresses lung cancer growth in vitro and in vivo. Since our data indicate that KRAS mutations can activate Mcl-1, we hypothesize that MI-223 alone or in combination with olaparib may be effective against lung cancers with KRAS mutations. MI-223-induced DSBs upregulate PD-L1 in tumor tissue from mutant KRAS driven lung cancer model, suggesting combination of MI- 223 with anti-PD-L1 may overcome PD-1 inhibitor resistance in KRAS-mutant lung cancer. To characterize and develop this novel Mcl-1 inhibitor MI-223 for the treatment of lung cancer, we propose two specific aims: (1) Determine whether and how KRAS mutations activate Mcl-1 leading to treatment resistance in human lung cancer cells. Studies will determine whether pMcl-1 at T163 is a novel prognostic biomarker and therapeutic target in patients with NSCLC; (2) Determine mechanism of action of novel Mcl-1 inhibitor MI-223 in killing human lung cancer cells. Studies will test the potency of MI-223 alone or in combination with PARP inhibitor olaparib in patient-derived lung cancer xenograft (PDX), radioresistant, and KRAS-mutant lung cancer xenografts. Determine whether MI-223 synergizes with olaparib or anti-PD-L1 to more effectively suppress tumor growth and prolong survival in genetically engineered mutant KRAS-driven lung cancer animal models. By targeting Mcl-1, we expect to develop a new class of anti-cancer agents and combination strategies for lung cancer treatment.

总结