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

• 批准号: 10316237
• 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
• 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/10316237
• 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; 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; Nonmetastatic; Oncogenic; Oral; PTPN11 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Phase I Clinical Trials; Phosphoric Monoester Hydrolases; Population; Positioning Attribute; Protein Tyrosine Kinase; Proteins; Proteome; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recurrent tumor; Relapse; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Son of Sevenless Proteins; Testing; Therapeutic; Treatment Efficacy; Work; Xenograft procedure; adduct; anti-tumor immune response; cancer cell; cancer therapy; cell type; checkpoint receptors; clinical efficacy; driver mutation; drug efficacy; exome; experimental study; gain of function; genome-wide; immune checkpoint; immunogenicity; improved; inhibitor; 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

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 转移性非小细胞肺癌（NSCLC）的治疗方法。含有 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，有效的、口服的、高度特异性的 SHP2 抑制剂被开发出来。这些药物抑制扩增的 RTK/PTK 融合驱动的细胞/肿瘤，并且 I 期临床试验。我们的结果表明，SHP2 抑制剂 (SHP2-Is) 可能在以下方面发挥更广泛的作用： 癌症治疗。 SHP2-Is 阻断 KRAS 突变和-WT 细胞对 MEK 抑制剂 (MEK-Is) 的适应性耐药性， 作用于鸟嘌呤核苷酸交换因子 (SOS1/2) 的上游。因此，SHP2-Is 具有单一代理 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。支持者 根据广泛的初步数据，我们假设 SHP2-Is 还将增强新开发的药物的功效 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 NSCLC，以及 Osi 对 Osi 敏感 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传导，并对 肿瘤微环境（TME）中的骨髓细胞和其他细胞。这些多效性作用定位了 SHP2 靶向治疗和免疫治疗的结合。该 MPI 应用程序与 SHP2 行动 (NEEL) 专家一起 NSCLC 转化生物学 (WONG) 阐明了 SHP2-Is 作为 NSCLC 治疗药物的效用。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型 SHP2-I 抗性 GEMM； (3) 分析复发性肿瘤并进行 CRISPR/Cas9 筛选以识别 对这些药物的耐药性。