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.

尽管靶向和免疫疗法的最新进展，但迫切需要新的治疗转移性非小细胞肺癌（NSCLC）的方法。含SH2结构域的磷酸酶-2 （SHP2）由PTPN11编码，是RAS/ERK MAP激酶所需的关键“正”信号组件受体酪氨酸激酶（RTK）和细胞因子受体的激活以及致癌的RTK 和蛋白 - 酪氨酸激酶（PTK）融合蛋白。最近，潜在的，口服的，高度特定的SHP2 开发了抑制剂。这些药物抑制了扩增的RTK/PTK融合驱动的细胞/肿瘤，并在 I期临床试验。我们的结果表明，SHP2抑制剂（SHP2-IS）在癌症治疗。 SHP2-IS阻滞对MEK抑制剂（MEK-I）的自适应性，KRAS突变和-WT细胞，在鸟嘌呤核交换因子上游作用（SOS1/2）。因此，shp2-is有单个代理对“循环” KRAS突变体（例如KRASG12C）的功效，该突变体保持了内在的GTPase活性。支持广泛的初步数据，我们假设SHP2-IS还将提高新发展的效率 G12C突变NSCLC中的KRASG12C（G12C）抑制剂，MEK-IS在Osimertinib（OSI）中的影响 - 抗性 EGFR突变NSCLC，以及OSI对OSI敏感的EGFR突变NSCLC的影响。 SHP2还结合免疫检查点受体（包括PD1）可能会抑制免疫受体信号，并对肿瘤微环境（TME）中的髓样细胞和其他细胞。这些多效动作位置SHP2 在靶向和免疫疗法的联系下。该MPI应用程序与SHP2 Action（NEEL）和 NSCLC转化生物学（WONG）阐明SHP2-IS作为NSCLC治疗的实用性。我们将：（1）测试 SHP2-I与共价rasg12c抑制剂，MEK-IS和EGFR抑制剂的组合在KRAS和EGFR抑制剂中 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，抗药性肿瘤细胞，免疫细胞耗竭和新的，可诱导的 shp2-耐药的宝石；（3）分析复发性肿瘤并执行CRISPR/CAS9筛选以识别对这些试剂的抵抗的景观。