Oncotarget

Research Papers:

The activation of SRC family kinases and focal adhesion kinase with the loss of the amplified, mutated EGFR gene contributes to the resistance to afatinib, erlotinib and osimertinib in human lung cancer cells

Yuichi Murakami, Kahori Sonoda, Hideyuki Abe, Kosuke Watari, Daiki Kusakabe, Koichi Azuma, Akihiko Kawahara, Jun Akiba, Chitose Oneyama, Jonathan A. Pachter, Kazuko Sakai, Kazuto Nishio, Michihiko Kuwano and Mayumi Ono _

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Oncotarget. 2017; 8:70736-70751. https://doi.org/10.18632/oncotarget.19982

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Abstract

Yuichi Murakami1,2,*, Kahori Sonoda1,*, Hideyuki Abe3, Kosuke Watari1, Daiki Kusakabe1,4, Koichi Azuma5, Akihiko Kawahara3, Jun Akiba3, Chitose Oneyama6, Jonathan A. Pachter7, Kazuko Sakai8, Kazuto Nishio8, Michihiko Kuwano2 and Mayumi Ono1

1Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

2Cancer Translational Research Center, St. Mary’s Institute of Health Sciences, Fukuoka, Japan

3Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan

4Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

5Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan

6Division of Microbiology and Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan

7Verastem Inc., Cambridge, MA, USA

8Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan

*These authors have contributed equally to this work

Correspondence to:

Mayumi Ono, email: [email protected]

Keywords: afatinib resistance, SRC family kinase, focal adhesion kinase, non-small cell lung cancer

Received: February 28, 2017    Accepted: July 18, 2017    Published: August 07, 2017

ABSTRACT

Second- and third-generation inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity (EGFR-TKIs) are improving the treatment of patients with non-small cell lung cancer. Here we established two sublines (BR1-8 and BR2-3) resistant to a second-generation inhibitor, afatinib, from the human lung cancer cell line HCC827 that harbors a mutation that activates the tyrosine kinase activity of EGFR. These afatinib-resistant sublines were resistant to first-generation EGFR-TKIs, gefitinib and erlotinib, and a third-generation EGFR-TKI, osimertinib. These resistant sublines showed markedly reduced levels of multiple EGFR family proteins, including the activated mutant EGFR, and complete loss of EGFR amplification as compared with their parental HCC827 cells harboring amplification of EGFR gene. Treatment with the multikinase inhibitor dasatinib or transfection with a SRC small interfering RNA inhibited cell survival and AKT phosphorylation in drug-resistant sublines to a greater extent compared with HCC827 cells. Further, the migration of drug-resistant cells was greater compared with that of HCC827 cells and was inhibited by dasatinib or an FAK inhibitor. These findings indicate that compensatory activation of SRC family kinases (SFKs) and FAK supports the survival and migration of afatinib-resistant cells when the expression of multiple EGFR family proteins was mostly abrogated. Combinations of potent drugs that target SFKs and FAK may overcome the resistance of lung cancer cells to second-generation TKIs.


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