Posts tagged PF-06463922
Effects of ALK inhibitors (PF-02341066 and PF-06463922) with radiotherapy in EML4 – ALK fusion positive (H2228 and 185IG) and negative (A549) experimental lung cancer cell lines
Effects of ALK inhibitors (PF-02341066 and PF-06463922) with radiotherapy in EML4 – ALK fusion positive (H2228 and 185IG) and negative (A549) experimental lung cancer cell lines

Purpose/Objective(s): The management of non-small cell lung cancer (NSCLC) patients with chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) is challenging. Indeed, the efficacy of the tyrosine kinase inhibitor (TKI) of novel generation may discuss the place of combined treatment with radiotherapy. We aimed to investigate the effects of combined radiotherapy and PF-02341066 or PF-06463922 in A549 and 185IG or H2228 cell lines, the former is a wild type ALK NSCLC model and the two latter are ALK-positive NSCLC models... Conclusion: In the current study, PF-02341066 induced notably cell cycle arrest at G2/M phase and PF-06463922 induced G1 arrest, in H2228 cells. Also, results suggest that the administration of PF-02341066 and PF-06463922 after irradiation could increase the induction of DNA damages due to IR in a panel of 3 NSCLC cell lines, compared to IR first followed by TKI treatment. These results could influence the clinical combination strategy for EML4 – ALK..... READ ARTICLE

International Journal of Radiation Oncology*Biology*Physics DOI:10.1016/j.ijrobp.2020.07.1599

Authors: D.N. Antoni, H. Burckel, G. Noel

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Case StudyKirk SmithALK inhibitors, PF-02341066, PF-06463922, radiotherapy, EML4 – ALK fusion, positive H2228 and 185IG, negative A549, experimental lung cancer cell lines
PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models
PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

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. READ ARTICLE

Cell Cancer DOI: 10.1016/j.ccell.2015.05.010

Authors: 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 and Tod Smeal

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Pre-ClinicalKirk Smithlorlatinib, G1202R, PF-06463922, ALK TKI