1. Academic Validation
  2. Antitumor activity of alectinib, a selective ALK inhibitor, in an ALK-positive NSCLC cell line harboring G1269A mutation: Efficacy of alectinib against ALK G1269A mutated cells

Antitumor activity of alectinib, a selective ALK inhibitor, in an ALK-positive NSCLC cell line harboring G1269A mutation: Efficacy of alectinib against ALK G1269A mutated cells

  • Cancer Chemother Pharmacol. 2016 Mar;77(3):623-8. doi: 10.1007/s00280-016-2977-y.
Yasushi Yoshimura 1 Mitsue Kurasawa 1 Keigo Yorozu 1 Oscar Puig 2 Walter Bordogna 3 Naoki Harada 4
Affiliations

Affiliations

  • 1 Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
  • 2 Pharma Early Research and Development, F. Hoffmann-La Roche, 430 East 29th Street, New York, NY, 10016, USA.
  • 3 Product Development, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • 4 Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan. haradanok@chugai-pharm.co.jp.
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.

Keywords

ALK; ALK G1269A mutation; Alectinib; Anaplastic lymphoma kinase; Resistance mutation.

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