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

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

doi:10.1016/j.ccell.2015.05.010

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

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

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

395 Citations (Scopus)

Résumé

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.

langue originale	Anglais
Pages (de - à)	70-81
Nombre de pages	12
journal	Cancer Cell
Volume	28
Numéro de publication	1
Les DOIs	https://doi.org/10.1016/j.ccell.2015.05.010
état	Publié - 13 juil. 2015
Modification externe	Oui

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10.1016/j.ccell.2015.05.010

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Zou, H. Y., Friboulet, L., Kodack, D. P., Engstrom, L. D., Li, Q., West, M., Tang, R. W., Wang, H., Tsaparikos, K., Wang, J., Timofeevski, S., Katayama, R., Dinh, D. M., Lam, H., Lam, J. L., Yamazaki, S., Hu, W., Patel, B., Bezwada, D., ... Smeal, T. (2015). PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell, 28(1), 70-81. https://doi.org/10.1016/j.ccell.2015.05.010

@article{1ddcd99b36c3404e86fcdb7e6833e13c,

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

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = jul,

day = "13",

doi = "10.1016/j.ccell.2015.05.010",

language = "English",

volume = "28",

pages = "70--81",

journal = "Cancer Cell",

issn = "1535-6108",

number = "1",

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Zou, HY, Friboulet, L, Kodack, DP, Engstrom, LD, Li, Q, West, M, Tang, RW, Wang, H, Tsaparikos, K, Wang, J, Timofeevski, S, Katayama, R, Dinh, DM, Lam, H, Lam, JL, Yamazaki, S, Hu, W, Patel, B, Bezwada, D, Frias, RL, Lifshits, E, Mahmood, S, Gainor, JF, Affolter, T, Lappin, PB, Gukasyan, H, Lee, N, Deng, S, Jain, RK, Johnson, TW, Shaw, AT, Fantin, VR & Smeal, T 2015, 'PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models', Cancer Cell, VOL. 28, Numéro 1, p. 70-81. https://doi.org/10.1016/j.ccell.2015.05.010

TY - JOUR

T1 - PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

AU - Zou, Helen Y.

AU - Friboulet, Luc

AU - Kodack, David P.

AU - Engstrom, Lars D.

AU - Li, Qiuhua

AU - West, Melissa

AU - Tang, Ruth W.

AU - Wang, Hui

AU - Tsaparikos, Konstantinos

AU - Wang, Jinwei

AU - Timofeevski, Sergei

AU - Katayama, Ryohei

AU - Dinh, Dac M.

AU - Lam, Hieu

AU - Lam, Justine L.

AU - Yamazaki, Shinji

AU - Hu, Wenyue

AU - Patel, Bhushankumar

AU - Bezwada, Divya

AU - Frias, Rosa L.

AU - Lifshits, Eugene

AU - Mahmood, Sidra

AU - Gainor, Justin F.

AU - Affolter, Timothy

AU - Lappin, Patrick B.

AU - Gukasyan, Hovhannes

AU - Lee, Nathan

AU - Deng, Shibing

AU - Jain, Rakesh K.

AU - Johnson, Ted W.

AU - Shaw, Alice T.

AU - Fantin, Valeria R.

AU - Smeal, Tod

PY - 2015/7/13

Y1 - 2015/7/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937521317&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2015.05.010

DO - 10.1016/j.ccell.2015.05.010

M3 - Article

C2 - 26144315

AN - SCOPUS:84937521317

SN - 1535-6108

VL - 28

SP - 70

EP - 81

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -