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

转染期间重排（RET）基因编码蛋白酪氨酸激酶（PTK）。RET像差 存在于各种人类癌症中。高效和选择性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后期。一个教训，从 以前的经验是，PTK靶向癌症治疗往往失败，因为适应性耐药性的演变， 从耐药的残留肿瘤中分离出来我们的初步研究结果表明，RET靶向癌症 治疗也不例外。为了延长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向突变，发现或开发药物 有效地对抗不同的耐药突变体，并发现替代信号机制，促进 肿瘤进展。本项目的总体目标是改善RET畸变的靶向治疗- 相关癌症该项目的目标是绘制耐药RET激酶的图谱， 突变，鉴定针对突变RET有效的药物，确定RET激酶变体的结构， 表征RET及其抑制剂之间相互作用的结构基础，并评估一种方法， 尽量减少肺部肿瘤残留具体目标1是鉴定和表征耐药的RET突变， 在临床前模型和癌症患者中选择性RET TKI，并发现潜在的次要药物。具体目标 2是确定耐药RET突变蛋白和RET抑制剂复合物的晶体结构。 具体目标3是在体内测试RET Mud敏感的TKI，并评价减少残留TKI的方法。 纤维化间质和相关的残留肿瘤细胞。总之，这项研究将提供一个RET突变- 用于精确管理RET异常癌症的TKI工具包，以最大限度地提高RET靶向癌症的获益 治疗，为开发多效RET TKI的连续管道奠定基础，并找到一种方法 减少耐药肿瘤的残留，延缓肿瘤复发。该项目的成果将 对延长癌症患者的生存期产生积极的转化影响。

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.