Ganetespib in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer

  • Anticancer Res. 2019 Apr;39(4):1767-1775. doi: 10.21873/anticanres.13283.
Eisuke Kurihara  1 ,  Kazuhiko Shien  2 ,  Hidejiro Torigoe  1 ,  Tatsuaki Takeda  3 ,  Yuta Takahashi  1 ,  Yusuke Ogoshi  1 ,  Takahiro Yoshioka  4 ,  Kei Namba  1 ,  Hiroki Sato  1 ,  Ken Suzawa  1 ,  Hiromasa Yamamoto  1 ,  Junichi Soh  1 ,  Mikio Okazaki  1 ,  Tadahiko Shien  1 ,  Shuta Tomida  5 ,  Shinichi Toyooka  1
Affiliations
  • 1. Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
  • 2. Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan [email protected].
  • 3. Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
  • 4. Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
  • 5. Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
PMID: 30952716 DOI: 10.21873/anticanres.13283
Abstract

Background: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in Cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 Inhibitor with a potent antitumor effect against various Cancer types.

Materials and methods: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung Cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition.

Results: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M.

Conclusion: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

Keywords
EGFR-TKI; HSP90 inhibitor; acquired drug resistance; ganetespib; non-small cell lung cancer.
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