Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Inoue Akira, Robinson Frederick S, Minelli Rosalba, Tomihara Hideo, Rizi Bahar Salimian, Rose Johnathon L, Kodama Takahiro, Srinivasan Sanjana, Harris Angela L, Zuniga Andy M, Mullinax Robert A, Ma Xiaoyan, Seth Sahil, Daniele Joseph R, Peoples Michael D, Loponte Sara, Akdemir Kadir C, Khor Tin Oo, Feng Ningping, Roszik Jason, Sobieski Mary M, Brunell David, Stephan Clifford, Giuliani Virginia, Deem Angela K, Shingu Takashi, Deribe Yonathan Lissanu, Menter David G, Heffernan Timothy P, Viale Andrea, Bristow Christopher A, Kopetz Scott, Draetta Giulio F, Genovese Giannicola, Carugo Alessandro
Аннотация
METHODS: To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC.
RESULTS: Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC.
CONCLUSIONS: Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.