The Activation of ERBB3 Signaling as a Resistance Mechanism to Targeted Therapies

ERBB3 信号传导的激活作为靶向治疗的耐药机制

• 批准号: 8011434
• 负责人: Jeffrey A. Engelman
• 金额: $ 34.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011434
• 关键词: Apoptosis; Applications Grants; Binding; Breast; Cancer Patient; Cancer cell line; Cell Death; Cell Line; Cell Survival; Cells; Clinical; Clinical Trials; Colon; Colon Carcinoma; Development; Diagnostic tests; Dose; EGFR gene; ERBB2 gene; ERBB3 gene; Environment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Erlotinib; Family member; Gefitinib; Genetic; Growth; Head and Neck Cancer; Health; In Vitro; In complete remission; Ligands; Lung; MAP Kinase Gene; MET gene; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; PI3K/AKT; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Physicians; Physiological; Protein Family; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Resistance; Resistance development; Rest; Science; Signal Pathway; Signal Transduction; Simulate; Specimen; Testing; Therapeutic; Tyrosine; United States; cancer cell; cellular engineering; cohort; design; effective therapy; in vivo; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; overexpression; partial response; public health relevance; resistance mechanism; therapy resistant; tumor

DESCRIPTION (provided by applicant): Therapies targeting the ERBB family members, EGFR and HER2, are commonly used for a wide range of epithelial cancers including lung, breast, colon and head and neck cancers. In a subset of these cancers, this provides substantial clinical benefit. Such cancers are unique in that they are "addicted" to ERBB signaling and either EGFR or HER2 controls critical growth and survival signaling pathways including PI3K/AKT, MAPK, and STAT. Previously, we and others observed that all cancer cells addicted to EGFR or HER2, are unique in that PI3K is activated by directly binding to tyrosine phosphorylated ERBB3, a kinase-dead ERBB family member (Engelman et al, PNAS, 2005). Thus, when these cancer cells are exposed to the appropriate ERBB inhibitor, ERBB3 phosphorylation is lost, PI3K and the other intracellular pathways are turned off, and the cancer cells undergo apoptosis. However, most, if not all patients, who initially develop a partial or complete response to an ERBB inhibitor will eventually develop progression of their cancer. Several groups including ours have found that a cancer becomes resistant to an ERBB inhibitor by finding a way to maintain PI3K/AKT signaling despite the presence of inhibitor. Recently, we modeled acquired resistance to EGFR kinase inhibitors by exposing EGFR-addicted cancer cell lines to increasing doses of inhibitor until the cells became resistant. In one of the resistant models, we found that the MET gene was amplified, and we validate this in lung cancer specimens that had become resistant to EGFR inhibitors (Engelman et al., Science, 2007). To our surprise, we found that the MET receptor tyrosine kinase caused resistance by maintaining phosphorylation of ERBB3 independently of EGFR and HER2. This was unexpected because previously only EGFR and HER2 were thought to be capable of phosphorylating ERBB3. Additionally, we found that MET signaling to ERBB3 was a pathway shared by all of the MET amplified cancer cell lines examined. When the gefitinib-resistant cells that developed MET amplification were treated with a combination of EGFR and MET inhibitors, there was obliteration of ERBB3 and AKT phosphorylation accompanied by marked cell death. This has spurred clinical trials testing a combination of MET and EGFR inhibitors for patients with acquired resistance to gefitinib or erlotinib. The finding that MET amplification activates ERBB3 phosphorylation independently of EGFR and HER2 suggests that it would be a potent resistance mechanism for other ERBB addicted cancers as well. In this grant application, we aim to determine if MET activation, via overexpression or ligand activation, maintains ERBB3/PI3K/AKT signaling and induces resistance to ERBB inhibitors in a broad range of EGFR and HER2 addicted cancers in vitro and in vivo. We will also determine if MET amplification is observed in patient cancer specimens that have developed resistance to ERBB targeted therapies. If MET amplification causes resistance in other ERBB driven cancers, this would immediately suggest diagnostic tests and therapeutic strategies for a wide range of cancers that become resistant to EGFR and HER2 directed therapies. PUBLIC HEALTH RELEVANCE: Metastatic lung, breast, colon and head and neck cancers are almost uniformly fatal and a very prominent cause of suffering in the United States and the rest of the world. Recently, therapies targeting the ERBB family proteins, EGFR and HER2, have been developed that effectively treat a subset of patients afflicted with these illnesses. Although these treatments are often initially effective, cancers invariably develop resistance to them. In this grant proposal, we aim to identify how these cancers become resistant so that we can design effective therapies to overcome this resistance and provide benefit to our patients.

描述（由申请人提供）：针对 ERBB 家族成员 EGFR 和 HER2 的疗法通常用于多种上皮癌，包括肺癌、乳腺癌、结肠癌和头颈癌。在这些癌症的一部分中，这提供了巨大的临床益处。此类癌症的独特之处在于它们对 ERBB 信号传导“上瘾”，并且 EGFR 或 HER2 控制关键的生长和生存信号传导途径，包括 PI3K/AKT、MAPK 和 STAT。此前，我们和其他人观察到，所有对 EGFR 或 HER2 成瘾的癌细胞都是独特的，因为 PI3K 通过直接结合酪氨酸磷酸化 ERBB3（一种激酶死亡的 ERBB 家族成员）而被激活（Engelman 等人，PNAS，2005）。因此，当这些癌细胞暴露于适当的 ERBB 抑制剂时，ERBB3 磷酸化消失，PI3K 和其他细胞内途径被关闭，癌细胞发生凋亡。然而，大多数（如果不是全部）最初对 ERBB 抑制剂产生部分或完全反应的患者最终会出现癌症进展。包括我们在内的几个研究小组发现，尽管存在抑制剂，但通过找到一种维持 PI3K/AKT 信号传导的方法，癌症会对 ERBB 抑制剂产生耐药性。最近，我们通过将 EGFR 成瘾的癌细胞系暴露于不断增加剂量的抑制剂直至细胞产生耐药性来模拟对 EGFR 激酶抑制剂的获得性耐药。在其中一个耐药模型中，我们发现 MET 基因被扩增，并且我们在对 EGFR 抑制剂产生耐药性的肺癌样本中验证了这一点（Engelman 等人，Science，2007）。令我们惊讶的是，我们发现 MET 受体酪氨酸激酶通过独立于 EGFR 和 HER2 维持 ERBB3 的磷酸化而引起耐药性。这是出乎意料的，因为之前认为只有 EGFR 和 HER2 能够磷酸化 ERBB3。此外，我们发现 MET 信号传导至 ERBB3 是所有检查的 MET 扩增癌细胞系共有的途径。当使用 EGFR 和 MET 抑制剂联合处理产生 MET 扩增的吉非替尼耐药细胞时，ERBB3 和 AKT 磷酸化被消除，并伴随着明显的细胞死亡。这促使临床试验针对吉非替尼或厄洛替尼获得性耐药的患者测试 MET 和 EGFR 抑制剂的组合。 MET 扩增独立于 EGFR 和 HER2 激活 ERBB3 磷酸化的发现表明，这也可能是其他 ERBB 成瘾癌症的有效耐药机制。在本次拨款申请中，我们的目标是确定 MET 激活是否通过过表达或配体激活来维持 ERBB3/PI3K/AKT 信号传导，并在体外和体内诱导多种 EGFR 和 HER2 成瘾癌症中对 ERBB 抑制剂的耐药性。我们还将确定是否在对 ERBB 靶向治疗产生耐药性的患者癌症标本中观察到 MET 扩增。如果 MET 扩增导致其他 ERBB 驱动的癌症产生耐药性，这将立即建议针对对 EGFR 和 HER2 定向疗法产生耐药性的多种癌症进行诊断测试和治疗策略。公共卫生相关性：转移性肺癌、乳腺癌、结肠癌和头颈癌几乎都是致命的，并且是美国和世界其他地区痛苦的一个非常重要的原因。最近，针对 ERBB 家族蛋白 EGFR 和 HER2 的疗法已经开发出来，可以有效治疗患有这些疾病的一部分患者。尽管这些治疗方法最初通常是有效的，但癌症总是会对它们产生耐药性。在这项拨款提案中，我们的目标是确定这些癌症如何产生耐药性，以便我们能够设计有效的疗法来克服这种耐药性并为我们的患者带来好处。