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Ref Type Journal Article
PMID (26144315)
Authors 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
Title PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models.
Journal Cancer cell
Vol 28
Issue 1
Date 2015 Jul 13
URL
Abstract Text 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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Lorlatinib Lorlatinib 106 8
Drug Name Trade Name Synonyms Drug Classes Drug Description
Lorlatinib Lorbrena PF-06463922 ALK Inhibitor 22 ROS1 Inhibitor 14 Lorbrena (lorlatinib) is a small molecule inhibitor of Alk and Ros1 fusion proteins, which may result in suppression of Alk and Ros1-mediated signaling thereby inhibiting cell growth and causing tumor regression (PMID: 26144315). Lorbrena (lorlatinib) is FDA approved for use in patients with ALK-positive non-small cell lung cancer (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and cell proliferation of transformed cells over expressing ALK F1174L in the context of EML4-ALK in culture (PMID: 26144315). 26144315
EML4 - ALK ALK G1202R lung cancer conflicting Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation, reduced proliferation, and induced apoptosis in transformed cells over expressing ALK G1202R in the context of EML4-ALK in culture and in cell line xenograft models (PMID: 26144315). 26144315
EML4 - ALK ALK V1180L lung non-small cell carcinoma sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation, reduced proliferation, and induced apoptosis of non-small cell lung carcinoma cells harboring ALK V1180L in the context of EML4-ALK in culture (PMID: 26144315). 26144315
EML4 - ALK ALK S1206Y Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and cell proliferation of transformed cells over expressing ALK S1206Y in the context of EML4-ALK in culture (PMID: 26144315). 26144315
EML4 - ALK ALK L1152R Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and cell proliferation of transformed cells over expressing ALK L1152R in the context of EML4-ALK in culture (PMID: 26144315). 26144315
EML4 - ALK ALK I1171T lung non-small cell carcinoma sensitive Lorlatinib Preclinical - Patient cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and cell growth in patient derived non-small cell lung cancer cells harboring ALK I1171T in the context of EML4-ALK in culture (PMID: 26144315). 26144315
EML4 - ALK ALK G1269A lung non-small cell carcinoma sensitive Lorlatinib Preclinical - Patient cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and growth of non-small cell lung cancer (NSCLC) cells over expressing ALK G1269A in the context of EML4-ALK in culture and in cell line xenograft models, as well as inhibited growth of patient derived NSCLC cells harboring EML4-ALK ALK G1269A in culture (PMID: 26144315). 26144315
EML4 - ALK lung non-small cell carcinoma sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and proliferation of non-small cell lung carcinoma cells harboring EML4-ALK fusion, and reduced intracranial tumor size in cell line xenograft models (PMID: 26144315). 26144315
EML4 - ALK ALK L1196M lung non-small cell carcinoma sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited Alk phosphorylation and proliferation of non-small cell lung carcinoma cells over expressing ALK L1196M in the context of EML4-ALK in culture, and resulted in tumor regression in cell line xenograft models (PMID: 26144315). 26144315