Abstract
Purpose
Alectinib is a highly selective next-generation anaplastic lymphoma kinase (ALK) inhibitor. Although alectinib shows inhibitory activity against various crizotinib-resistant ALK mutations in studies using cell-free kinase assays and Ba/F3 cell-based assays, it has not been tested for efficacy against non-small cell lung cancer (NSCLC) with the ALK mutations.
Methods
We conducted in vitro and in vivo investigations into the antitumor activity of alectinib against an ALK-positive NSCLC cell line, SNU-2535, which harbors an ALK G1269A mutation. The clinical efficacy of alectinib against a NSCLC patient harboring ALK G1269A mutation was evaluated in the phase I part of the North American study.
Results
Alectinib exhibited antiproliferative activity against SNU-2535 cells in vitro with IC50 of 33.1 nM. Alectinib strongly inhibited phosphorylation of ALK and its downstream signaling molecules ERK1/2, AKT, and STAT3. In a mouse xenograft model, once-daily oral administration of alectinib for 21 days resulted in strong tumor regression. In addition, administration of alectinib for 100 days achieved continuous tumor regression without tumor regrowth in all mice. Notably, eradication of tumor cells was observed in half of the mice. In the clinical study, a patient with ALK G1269A mutation showed partial response to alectinib with a duration of response of 84 days.
Conclusion
These results indicated that alectinib has potent antitumor activity against NSCLC cells harboring the crizotinib-resistant mutation ALK G1269A. It is expected that alectinib would provide a valuable therapeutic option for patients with NSCLC having not only native ALK but also crizotinib-resistant ALK mutations.
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References
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H (2007) Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566. doi:10.1038/nature05945
Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O’Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Janne PA (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368(25):2385–2394. doi:10.1056/NEJMoa1214886
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, Tursi J, Blackhall F, Investigators P (2014) First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371(23):2167–2177. doi:10.1056/NEJMoa1408440
Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, Ishikawa Y, Kimura H, Mitsudomi T, Tanio Y, Mano H (2010) EML4–ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363(18):1734–1739. doi:10.1056/NEJMoa1007478
Isozaki H, Takigawa N, Kiura K (2015) Mechanisms of acquired resistance to ALK inhibitors and the rationale for treating ALK-positive lung cancer. Cancers 7(2):763–783. doi:10.3390/cancers7020763
Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y (2011) CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 19(5):679–690. doi:10.1016/j.ccr.2011.04.004
Kodama T, Hasegawa M, Takanashi K, Sakurai Y, Kondoh O, Sakamoto H (2014) Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol 74(5):1023–1028. doi:10.1007/s00280-014-2578-6
Kodama T, Tsukaguchi T, Yoshida M, Kondoh O, Sakamoto H (2014) Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett 351(2):215–221. doi:10.1016/j.canlet.2014.05.020
Katayama R, Lovly CM, Shaw AT (2015) Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Cancer Res 21(10):2227–2235. doi:10.1158/1078-0432.CCR-14-2791
Kim S, Kim TM, Kim DW, Go H, Keam B, Lee SH, Ku JL, Chung DH, Heo DS (2013) Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol 8(4):415–422. doi:10.1097/JTO.0b013e318283dcc0
Yamashita-Kashima Y, Iijima S, Yorozu K, Furugaki K, Kurasawa M, Ohta M, Fujimoto-Ouchi K (2011) Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res 17(15):5060–5070. doi:10.1158/1078-0432.ccr-10-2927
Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, Morcos PN, Lee RM, Garcia L, Yu L, Boisserie F, Di Laurenzio L, Golding S, Sato J, Yokoyama S, Tanaka T, Ou SH (2014) Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib–resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 15(10):1119–1128. doi:10.1016/s1470-2045(14)70362-6
Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T (2013) CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol 14(7):590–598. doi:10.1016/S1470-2045(13)70142-6
Iwama E, Takayama K, Harada T, Okamoto I, Ookubo F, Kishimoto J, Baba E, Oda Y, Nakanishi Y (2015) Highly sensitive and quantitative evaluation of the EGFR T790M mutation by nanofluidic digital PCR. Oncotarget 6(24):20466–20473. doi:10.18632/oncotarget.4058
Acknowledgments
The authors thank Marie Mochizuki for the in vitro cell proliferation assay and immunoblotting; Junko Fukumura for the in vivo experiments; Ikuno Sugimoto for the histological experiments; Dr. Yoichiro Moriya for help in manuscript preparation; and Dr. Kaori Fujimoto-Ouchi for helpful discussion and advice regarding this study.
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Authors are employees of Chugai Pharmaceutical Co., Ltd or F. Hoffman-La Roche. The authors declare that they have no conflict of interest.
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Yoshimura, Y., Kurasawa, M., Yorozu, K. et al. Antitumor activity of alectinib, a selective ALK inhibitor, in an ALK-positive NSCLC cell line harboring G1269A mutation. Cancer Chemother Pharmacol 77, 623–628 (2016). https://doi.org/10.1007/s00280-016-2977-y
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DOI: https://doi.org/10.1007/s00280-016-2977-y