Investigating Resistance Mechanisms to Non-covalent Bruton's Tyrosine Kinase Inhibitors and Therapeutic Approaches to Overcome Resistance for Patients with B-Cell Malignancies

项目总结 B细胞恶性肿瘤，如慢性淋巴细胞白血病(CLL)和其他形式的非霍奇金 淋巴瘤(NHL)是一种常见的血液系统恶性肿瘤，通常发生在成年人。这些恶性肿瘤 起源于功能失调的成熟B细胞。B细胞受体(BCR)通路的异常信号可导致 布鲁顿氏酪氨酸(BTK)是BCR早期的一种激酶，B细胞恶性肿瘤的增殖和存活 途径，癌症治疗的一个有吸引力的靶点。虽然现有的治疗方法可以缓解疾病， 几乎所有患者都会复发，这导致了人们的共识，即CLL仍然被认为是一种不治之症。 BTK的共价(不可逆)小分子抑制剂，如伊布鲁替尼，已经改变了管理 CLL、套细胞淋巴瘤(MCL)和Waldenström巨球蛋白血症(WM)。共价BTK抑制剂 对多发性B细胞恶性肿瘤有效，但由于耐药性和耐受性，许多患者 停止使用这些代理。为了克服这些问题，高度选择性和可逆的非共价BTK 已经开发出了抑制剂。它们目前正在临床试验中进行测试，显示出安全性和前景 对多种B细胞肿瘤的疗效，包括高度预治疗的CLL、MCL、WM和滤泡性淋巴瘤， 证明非共价BTK抑制剂可能解决对替代疗法日益增长的未得到满足的需求 对这些病人来说。尽管吡妥布替尼的有益特征和高总有效率在 1期研究，一些曾接受CLL和B细胞恶性肿瘤治疗的患者对 治疗或对单一治疗有初步反应后复发。 基于对BTK、PLCG2和其他重复突变基因的下一代突变分析 在非共价BTK抑制剂治疗之前和治疗进展期间，我们现在有 确定了新的BTK和PLCG2变种，只有在治疗后才能检测到。鉴于这些初步情况 发现，我假设BTK或B细胞受体信号通路中的靶点突变(如 PLCG2突变)导致对非共价BTK抑制和结合BTK的抗性 与其他CLL靶向药物一起使用的抑制剂将绕过上述耐药性。目前，还没有任何报告 研究患者对非共价BTK抑制剂的耐药机制。这项提案将确定这些机制 通过这种机制，细胞对非共价BTK抑制产生抵抗力，并通过额外的 以下目标的靶向治疗：目标1：确定新的BTK突变的机制 观察到对非共价BTK抑制的获得性抵抗。目标2：测试要克服的联合疗法 B细胞淋巴瘤对BTK抑制剂的耐药性。由于以下原因，对治疗方法的需求呈指数级增长 获得性耐药患者的发生率增加。这项研究的结果将产生重大影响 适用于患有多种B细胞恶性肿瘤的患者。此外，这些发现将为以下发展提供信息 非共价BTK抑制剂的合理联合治疗。

PROJECT SUMMARY B-cell malignancies such as chronic lymphocytic leukemia (CLL) and other forms of Non-Hodgkin lymphomas (NHL) are common hematologic malignancies typically occurring in adults. These malignancies arise from dysfunctional, mature B-cells. Irregular signaling of the B-Cell receptor (BCR) pathway can lead to proliferation and survival of B-cell malignancies making Bruton’s tyrosine (BTK), a kinase early in the BCR pathway, an attractive target for cancer therapy. While available treatments can lead to disease remission, nearly all patients relapse, leading to the consensus that CLL remains to be considered an incurable disease. Covalent (irreversible) small molecule inhibitors of BTK, such as ibrutinib, have transformed the management of CLL, mantle cell lymphoma (MCL), and Waldenström’s Macroglobulinemia (WM). Covalent BTK inhibitors are efficacious in multiple B-cell malignancies, however due to resistance and intolerance, many patients discontinue these agents. To overcome these problems, highly selective and reversible non-covalent BTK inhibitors have been developed. They are currently being tested in clinical trials showing safety and promising efficacy in multiple B-cell neoplasms, including heavily pre-treated CLL, MCL, WM, and follicular lymphoma, demonstrating that non-covalent BTK inhibitors might address a growing unmet need for alternative therapies for these patients. Despite the beneficial features of pirtobrutinib and a high overall response rate seen in the Phase 1 studies, some patients with previously treated CLL and B-cell malignancies did not respond to treatment or relapsed after initial response to monotherapy. Based on next-generation mutational analysis of BTK, PLCG2, and additional genes recurrently mutated in CLL prior to non-covalent BTK inhibitor therapy and at the time of on treatment progression, we have now identified novel BTK and PLCG2 variants that were only detectable post-treatment. Given these preliminary findings, I hypothesize that on-target mutations within BTK or the B-cell receptor signaling pathway (such as PLCG2 mutations) result in resistance to non-covalent BTK inhibition and that combining BTK inhibitors with other CLL targeting drugs will circumvent said resistance. Currently, there are no reports of resistance mechanisms to non-covalent BTK inhibitors in patients. This proposal will identify the mechanisms by which cells develop resistance to non-covalent BTK inhibition and challenge that resistance with additional targeted therapies in the following aims: Aim 1: Identify the mechanism underlying novel BTK mutations observed in acquired resistance to non-covalent BTK inhibition. Aim 2: Test combination therapies to overcome resistance to BTK inhibitors in B-cell lymphoma. There is an exponential need for therapeutic alternatives due to an increased incidence of patients with acquired resistance. The results of this study will have a major impact for patients with a variety of B-cell malignancies. Additionally, these findings will inform the development of rational combination therapies with non-covalent BTK inhibitors.