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: 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
• 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

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.

尽管最近在靶向和免疫治疗方面取得了进展，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SH 2结构域磷酸酶-2 由PTPN 11编码的SHP 2是RAS/ERK MAP激酶所需的关键“正”信号传导组分， 通过受体酪氨酸激酶（RTK）和细胞因子受体以及致癌扩增的RTK激活 和蛋白质-酪氨酸激酶（PTK）融合蛋白。最近，强效、口服、高度特异性的SHP 2 开发了抑制剂。这些试剂抑制扩增的RTK/RTK融合驱动的细胞/肿瘤，并且在 I期临床试验。我们的研究结果表明，SHP 2-抑制剂（SHP 2-Is）可能具有更广泛的作用， 癌症治疗SHP 2-Is阻断KRAS突变体和WT细胞中对MEK抑制剂（MEK-Is）的适应性抗性， 作用于鸟嘌呤核苷酸交换因子（SOS 1/2）的上游。因此，SHP 2 - 1具有单一药剂 针对“循环”KRAS突变体（例如，KRASG 12 C），其保留了固有的GT3活性。支持 根据广泛的初步数据，我们假设SHP 2-Is也将增强新开发的抗肿瘤药物的功效。 KRASG 12 C（G12 C）抑制剂在G12 C突变型NSCLC中的作用，MEK-Is在奥希替尼（Osi）耐药型NSCLC中的作用 EGFR突变型NSCLC，以及Osi在Osi敏感性EGFR突变型NSCLC中的作用。SHP 2也结合免疫 包括PD 1在内的检查点受体可能抑制免疫受体信号传导，并对免疫应答具有复杂的影响。 骨髓细胞和肿瘤微环境（TME）中的其他细胞。这些多效性作用使SHP 2 靶向治疗和免疫治疗的关系。这个MPI应用程序加入了SHP 2行动（NEEL）的专家， NSCLC转化生物学（WONG），以阐明SHP 2-Is作为NSCLC治疗剂的效用。我们将：（1）测试 SHP 2 - 1 s与共价RASG 12 C抑制剂、MEK-1 s和EGFR-抑制剂的组合， EGFR突变型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可诱导的 SHP 2-I抗性GEMM;和（3）分析复发肿瘤并进行CRISPR/Cas9筛选以鉴定肿瘤的免疫原性。 对这些代理人的抵抗。