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

尽管最近在靶向和免疫治疗方面取得了进展，但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Sh2结构域的磷酸酶-2 (Shp2)由PTPN11编码，是Ras/ERK MAP激酶所需的一个关键的“正”信号成分 受体酪氨酸激酶(RTK)和细胞因子受体以及致癌基因扩增的RTK的激活 和蛋白-酪氨酸激酶(PTK)融合蛋白。最近，有效的，口服的，高度特异的SHP2 抑制剂被开发出来了。这些药物抑制放大的RTK/PTK融合驱动的细胞/肿瘤，并在 I期临床试验。我们的结果提示SHP2-抑制物(SHP2-IS)可能在 癌症治疗。Shp2-IS阻断KRAS突变体和-WT细胞对MEK抑制剂(MEK-IS)的适应性抵抗， 作用于鸟嘌呤核苷酸交换因子的上游(SOS1/2)。因此，SHP2-IS具有单一试剂 对“循环”的KRAS突变体(例如，KRASG12C)的有效性，这些突变体保留了固有的GTP酶活性。支持： 大量的初步数据，我们假设SHP2-IS也将增强新开发的疗效 KRASG12C(G12C)抑制剂在G12C突变的NSCLC中的作用，MEK-IS在奥西莫替尼(Osimertinib，Osi)耐药中的作用 EGFR突变的NSCLC，以及Osi对EGFR敏感的NSCLC的影响。Shp2也能结合免疫 检查点受体，包括PD1，可能抑制免疫受体信号转导，并对 肿瘤微环境(TME)中的髓系细胞和其他细胞。这些多效性作用使SHP2 在靶向治疗和免疫治疗的结合点。这款MPI应用程序加入了SHP2行动(Neel)和 NSCLC翻译生物学(Wong)，以阐明SHP2-IS作为非小细胞肺癌治疗的效用。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突变的NSCLC GEMM；(2)阐明这些组合的细胞自主和非自主效应 使用最先进的免疫分析，耐药肿瘤细胞，免疫细胞耗竭和新的，可诱导的 以及(3)分析复发肿瘤并进行CRISPR/Cas9筛查以确定 对这些药物的抵抗力。

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.