PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

Zou Helen Y.; Friboulet Luc; Kodack David P.; Engstrom Lars D.; Li Qiuhua; West Melissa; Tang Ruth W.; Wang Hui; Tsaparikos Konstantinos; Wang Jinwei; Timofeevski Sergei; Katayama Ryohei; Dinh Dac M.; Lam Hieu; Lam Justine L.; Yamazaki Shinji; Hu Wenyue; Patel Bhushankumar; Bezwada Divya; Frias Rosa L.; Lifshits Eugene; Mahmood Sidra; Gainor Justin F.; Affolter Timothy; Lappin Patrick B.; Gukasyan Hovhannes; Lee Nathan; Deng Shibing; Jain Rakesh K.; Johnson Ted W.; Shaw Alice T.; Fantin Valeria R.; Smeal Tod

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PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

机译：PF-06463922，一种ALK / ROS1抑制剂，在临床前模型中克服了对第一代和第二代ALK抑制剂的耐药性

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We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.

机译：我们报告PF-06463922，一种有效的和脑渗透ALK / ROS1抑制剂的临床前评价。与其他临床可用的ALK抑制剂相比，PF-06463922对所有已知的临床获得的ALK突变，包括高耐药性G1202R突变体，均显示出优异的效力。此外，PF-06463922治疗以优异的方式导致了EML4-ALK驱动的脑转移的消退，从而延长了小鼠的存活时间。最后，PF-06463922在各种临床前研究中均显示出较高的选择性和安全性。这些结果表明，PF-06463922将对ALK驱动的肺癌患者高度有效，包括那些由于继发性ALK激酶结构域突变和/或脑转移而在临床上可用的ALK抑制剂复发的患者。

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《Cancer Cell》 |2015年第1期|共12页
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Zou Helen Y.; Friboulet Luc; Kodack David P.; Engstrom Lars D.; Li Qiuhua; West Melissa; Tang Ruth W.; Wang Hui; Tsaparikos Konstantinos; Wang Jinwei; Timofeevski Sergei; Katayama Ryohei; Dinh Dac M.; Lam Hieu; Lam Justine L.; Yamazaki Shinji; Hu Wenyue; Patel Bhushankumar; Bezwada Divya; Frias Rosa L.; Lifshits Eugene; Mahmood Sidra; Gainor Justin F.; Affolter Timothy; Lappin Patrick B.; Gukasyan Hovhannes; Lee Nathan; Deng Shibing; Jain Rakesh K.; Johnson Ted W.; Shaw Alice T.; Fantin Valeria R.; Smeal Tod;
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1. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models [J] . Zou Helen Y., Friboulet Luc, Kodack David P., Cancer Cell . 2015,第1期

机译：PF-06463922，一种ALK / ROS1抑制剂，在临床前模型中克服了对第一代和第二代ALK抑制剂的耐药性
2. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models [J] . Zhang Sen, Anjum Rana, Squillace Rachel, Clinical cancer research: an official journal of the American Association for Cancer Research . 2016,第22期

机译：强大的ALK抑制剂Brigatinib（AP26113）在临床前模型中克服了对第一代和第二代ALK抑制剂的耐药机制
3. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models [J] . Zhang Sen, Anjum Rana, Squillace Rachel, Clinical cancer research: an official journal of the American Association for Cancer Research . 2016,第22期

机译：强大的ALK抑制剂Brigatinib（AP26113）在临床前模型中克服了对第一代和第二代ALK抑制剂的耐药机制
4. High throughput multiplexed phosphoproteomics identifies drivers of resistance to ALK inhibitor treatment in lung cancer [C] . Amanda L. Edwards, Luc Friboulet, Rosa Frias, ASMS Conference on Mass Spectrometry and Allied Topics . 2016

机译：高通量复用磷蛋白酶鉴定肺癌抗华抗抑制剂治疗的驱动因素
5. Localization-based Signaling Pathway Dependence of ROS1 Fusions and a Novel Role for Ras in EML4-ALK-Driven Lung Cancer [D] . Neel, Dana Sarabeth. 2017

机译：ROS1融合的基于本地化的信号通路依赖性和在EML4-ALK驱动的肺癌中Ras的新作用。
6. PF-06463922 an ALK/ROS1 inhibitor overcomes resistance to 1st and 2nd generation ALK inhibitors in pre-clinical models [O] . Helen Y. Zou, Luc Friboulet, David P. Kodack, -1

机译：PF-06463922一种ALK / ROS1抑制剂在临床前模型中克服了对第一代和第二代ALK抑制剂的耐药性
7. PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models [O] . Zou Helen Y., Friboulet Luc, Kodack David P., 2015

机译：PF-06463922，一种ALK / ROS1抑制剂，在临床前模型中克服了对第一代和第二代ALK抑制剂的耐药性

PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

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