Blocking tumor progression in therapy-responsive RET aberration-associated cancer

转染期重排(RET)基因编码蛋白酪氨酸激酶(PTK)。RET像差 在各种类型的人类癌症中都有发现。高效选择性RET蛋白酪氨酸激酶抑制剂 (TKI)正处于精确癌症治疗的临床开发的后期阶段。从这一事件中吸取的教训 以往的经验是，以PTK为靶点的癌症治疗经常因为适应性抵抗的进化而失败 来自耐药、残留的肿瘤。我们的初步研究结果表明，RET靶向的癌症 治疗对这一规则也不例外。为了延长对肿瘤的抑制和患者的生命，我们必须 消除残留的肿瘤细胞，识别导致耐药性的靶基因突变，发现或开发药物 有效对抗不同的耐药突变，并发现促进 肿瘤进展。该项目的总体目标是改进RET像差的靶向治疗- 相关癌症。这个项目的目标是绘制耐药RET激酶的图景 突变，鉴定有效对抗突变RET的药物，确定RET激酶变异体的结构， 表征RET与其抑制剂相互作用的结构基础，并评价一种方法 最大限度地减少残留的肺部肿瘤。具体目标1是鉴定和表征RET突变对 在临床前模型和癌症患者中选择RET TKI，并寻找潜在的辅助药物。特定目标 2确定耐药RET突变蛋白和RET抑制物复合体的晶体结构。 具体目标3是在体内测试RET突变敏感的TKI，并评估减少残留的方法 纤维间质和相关的残留肿瘤细胞。综上所述，这项研究将提供RET突变- TKI工具包，用于RET异常癌症的精确管理，以最大限度地提高RET靶向癌症的益处 治疗，为开发连续的突变有效的RET TKI奠定基础，并找到一种方法 减少残留耐药肿瘤，延缓肿瘤复发。这个项目的成果将会有 对延长癌症患者的生存期有积极的翻译作用。

The rearranged during transfection (RET) gene encodes a protein tyrosine kinase (PTK). RET aberrations are found in various types of human cancer. Highly potent and selective RET protein tyrosine kinase inhibitors (TKIs) are in the later stage of clinical development for precision cancer treatment. A lesson learned from the previous experience is that the PTK-targeted cancer therapy often fails because of adaptive resistance evolved from the drug-tolerant, residual tumors. Results of our preliminary studies indicate that the RET-targeted cancer treatment is no exception to this rule. To prolong the suppression of tumors and the lives of patients, we must eliminate the residual tumor cells, identify target mutations that cause drug resistance, find or develop drugs effective against different drug-resistant mutants, and discover alternative signaling mechanisms that promote tumor progression. The overall goal of this project is to improve the targeted therapy for RET aberration- associated cancer. The objectives of this project are to map the landscape of drug-resistant RET kinase mutations, identify drugs effective against mutant RET, determine the structures of RET kinase variants, characterize the structural bases of interaction between RET and its inhibitors, and evaluate a method to minimize the residual lung tumors. Specific Aim 1 is to identify and characterize RET mutations resistant to selective RET TKIs in preclinical models and cancer patients, and find potential secondary drugs. Specific Aim 2 is to determine the crystal structures of drug-resistant RET mutant proteins and RET-inhibitor complexes. Specific Aim 3 is to test RET mutant-sensitive TKIs in vivo and evaluate a method for reducing the residual fibrotic stroma and the associated residual tumor cells. Taken together, this study will provide a RET mutation- TKI toolkit for precision management of RET-aberrant cancers to maximize the benefit of RET-targeted cancer therapy, lay the foundation for developing a continuous pipeline of mutant-effective RET TKIs, and find a method to reduce the residual drug-tolerant tumors to delay tumor recurrence. The outcomes of this project will have positive translational impact on prolonging the survival of patients with cancer.