Response and resistance to SHP2 inhibitors alone and in combination in Non-Small Cell Lung Cancer

非小细胞肺癌中单独使用和联合使用 SHP2 抑制剂的反应和耐药性

基本信息

批准号：
10531929
负责人：
BENJAMIN G. NEEL
金额：
$ 68.8万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-10 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531929
关键词：
Affect Allografting Apoptosis Binding Biology CRISPR screen CRISPR/Cas technology Cancer Biology Cells Chimeric Proteins Clinic Color Complex Cytokine Receptors Data Disease Drug resistance Ensure Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Extracellular Signal Regulated Kinases Family Flow Cytometry Genetically Engineered Mouse Genomics Genotype Goals Growth Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Immune Immune checkpoint inhibitor Immunologic Receptors Immunology procedure Immunotherapy In Vitro Infiltration KRAS2 gene Kinetics Life Locales Lymphoid Cell MEKs Malignant Neoplasms Malignant neoplasm of lung Modality Molecular Mus Mutation Myeloid Cells Non-Small-Cell Lung Carcinoma Oncogenic Oral PTPN11 gene Pathway interactions Patient-Focused Outcomes Patients Peptides Phase I Clinical Trials Phosphoric Monoester Hydrolases Population Positioning Attribute Proliferating Protein Tyrosine Kinase Proteins Proteome Publishing Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Recurrent tumor Relapse Resistance Resistance development Role Signal Pathway Signal Transduction Testing Therapeutic Treatment Efficacy Tyrosine Kinase Receptor Inhibition Work Xenograft procedure adduct anti-tumor immune response cancer cell cancer therapy cell type checkpoint receptors clinical efficacy driver mutation drug efficacy efficacy evaluation exome experimental study gain of function genome-wide immune checkpoint immunogenicity improved inhibitor loss of function mutant neoplastic cell new combination therapies novel therapeutic intervention novel therapeutics phase I trial prevent programmed cell death protein 1 protein phosphatase inhibitor-2 resistance mechanism resistance mutation response scaffold senescence src Homology Region 2 Domain targeted treatment transcriptome tumor tumor growth tumor microenvironment

项目摘要

Despite recent advances in targeted and immune-therapies, there is an urgent need for new therapeutic approaches for metastatic non-small cell lung cancer (NSCLC). SH2 domain-containing phosphatase-2 (SHP2), encoded by PTPN11, is a key “positive” signaling component, required for RAS/ERK MAP kinase activation by receptor tyrosine kinases (RTKs) and cytokine receptors, as well as by oncogenic amplified RTKs and protein-tyrosine kinase (PTK) fusion proteins. Recently, potent, orally available, highly specific SHP2 inhibitors were developed. These agents inhibit amplified RTK/PTK-fusion-driven cells/tumors and are in Phase I clinical trials. Our results suggest that SHP2-inhibitors (SHP2-Is) could have a much broader role in cancer therapy. SHP2-Is block adaptive resistance to MEK inhibitors (MEK-Is) in KRAS-mutant and -WT cells, acting upstream of guanine nucleotide exchange factors (SOS1/2). Consequently, SHP2-Is have single agent efficacy against “cycling” KRAS mutants (e.g., KRASG12C), which retain intrinsic GTPase activity. Supported by extensive Preliminary Data, we hypothesize that SHP2-Is will also enhance the efficacy of newly developed KRASG12C (G12C) inhibitors in G12C-mutant NSCLC, the effects of MEK-Is in Osimertinib (Osi)-resistant EGFR- mutant NSCLC, and the effects of Osi in Osi-sensitive EGFR-mutant NSCLC. SHP2 also binds immune checkpoint receptors, including PD1, might inhibit immune receptor signaling, and has complex effects on myeloid cells and other cells in the tumor microenvironment (TME). These pleiotropic actions position SHP2 at the nexus of targeted and immune therapies. This MPI application joins experts in SHP2 action (NEEL) and NSCLC translational biology (WONG) to clarify the utility of SHP2-Is as NSCLC therapeutics. We will: (1) test combinations of SHP2-Is with covalent RASG12C inhibitors, MEK-Is, and EGFR-inhibitors in KRAS- and EGFR-mutant NSCLC GEMMs; (2) clarify cell-autonomous and non-autonomous effects of these combinations using state-of-the art immune assays, drug-resistant tumor cells, immune cell depletion and new, inducible SHP2-I-resistant GEMMs; and (3) analyze recurrent tumors and perform CRISPR/Cas9 screens to identify the landscape of resistance to these agents.

尽管靶向治疗和免疫治疗最近取得了进展，但仍迫切需要新的治疗方法含有 SH2 结构域的磷酸酶 2 的转移性非小细胞肺癌 (NSCLC) 的治疗方法。 (SHP2) 由 PTPN11 编码，是 RAS/ERK MAP 激酶所需的关键“正”信号传导成分由受体酪氨酸激酶 (RTK) 和细胞因子受体以及致癌扩增 RTK 激活和蛋白质酪氨酸激酶 (PTK) 融合蛋白最近出现了有效的、口服的、高度特异性的 SHP2。这些药物可抑制扩增的 RTK/PTK 融合驱动的细胞/肿瘤。我们的 I 期临床试验结果表明，SHP2 抑制剂 (SHP2-Is) 可能具有更广泛的作用。 SHP2-Is 阻断 KRAS 突变和-WT 细胞对 MEK 抑制剂 (MEK-Is) 的适应性耐药， SHP2-Is 作用于鸟嘌呤核苷酸交换因子 (SOS1/2) 的上游，具有单一试剂。针对“循环”KRAS 突变体（例如 KRASG12C）的功效，该突变体保留了内在的 GTP 酶活性。根据广泛的初步数据，我们发现 SHP2-Is 还将增强新开发的功效 KRASG12C (G12C) 抑制剂在 G12C 突变 NSCLC 中的作用，MEK-Is 在奥希替尼 (Osi) 耐药中的作用 EGFR 突变型 NSCLC，Osi 在 Osi 敏感的 EGFR 突变型 NSCLC 中的作用也与免疫结合。检查点受体，包括 PD1，可能会抑制免疫受体信号传导，并对免疫系统产生复杂的影响这些多效性作用对 SHP2 进行定位。该 MPI 应用程序结合了 SHP2 作用 (NEEL) 和免疫疗法的专家。 NSCLC 转化生物学 (WONG) 旨在阐明 SHP2-Is 作为 NSCLC 疗法的效用。我们将：(1) 测试。 SHP2-Is 与共价 RASG12C 抑制剂、MEK-Is 和 EGFR 抑制剂在 KRAS 和 EGFR 突变 NSCLC GEMM；(2) 阐明这些组合的细胞自主和非自主效应使用最先进的免疫测定、耐药肿瘤细胞、免疫细胞耗竭和新的诱导性 SHP2-I 抗性 GEMM；(3) 分析复发肿瘤并进行 CRISPR/Cas9 筛选以鉴定对这些药物的耐药性。