Targeting vulnerabilities of therapy-resistant cancer cell states with small molecules

摘要 靶向治疗和免疫治疗是治疗中最具变革性和最有前途的两项进展。 癌症治疗在过去的二十年里。然而，像传统的化疗一样，它们经常屈服于 癌症最终抵抗对其脆弱性的治疗攻击的能力， 对这些治疗的临床反应令人印象深刻。该项目的重点是保守的非突变 耐药机制，经常遇到的耐药出现在多种治疗 多种癌症类型的治疗方案。在CTD2网络的当前阶段，我们开发了功能强大的新 使社区能够识别新的癌症脆弱性的工具和能力。该方法依赖于 癌症治疗响应门户（CTRP），其中包含定量化合物的大型数据集 敏感性数据，并已无限制地提供。使用CTRP，我们发现了 存在至少一种这种常见的治疗抗性状态，与间充质特征相关， 癌细胞重要的是，这种状态出现在化疗或靶向治疗的治疗中 在几种癌症类型中。该项目旨在充分剖析这一途径，并发现其他此类途径。 途径，了解抵抗状态脆弱性的基础，并学习如何利用它们 安全有效的治疗方法。

ABSTRACT Targeted therapies and immunotherapies are two of the most transformative and promising advances in cancer treatment over the last two decades. Yet they, like conventional chemotherapies, frequently succumb to the ability of cancers eventually to resist therapeutic attacks on their vulnerabilities, reversing the initially impressive clinical responses to these treatments. This project focuses on conserved non-mutational mechanisms of resistance that are frequently encountered in resistance arising in multiple therapeutic regimens across multiple cancer types. In the current phase of the CTD2 Network, we developed powerful new tools and capabilities that enable the community to identify novel cancer vulnerabilities. The method relies on the Cancer Therapeutics Response Portal (CTRP), which houses a large dataset of quantitative compound sensitivity data and has been made available without restriction. Using CTRP, we found evidence for the existence of at least one such common therapy-resistant state, associated with mesenchymal characteristics of cancer cells. Importantly, this state emerges from treatment with either chemotherapy or targeted therapeutics across several cancer types. This project aims to fully dissect this pathway, and to discover other such pathways, to understand the bases of resistant-state vulnerabilities, and to learn how to exploit them therapeutically in a safe and effective way.