2. Academic Validation
  3. 3D layered co-culture model enhances Trastuzumab Deruxtecan sensitivity and reveals the combined effect with G007-LK in HER2-positive non-small cell lung cancer

3D layered co-culture model enhances Trastuzumab Deruxtecan sensitivity and reveals the combined effect with G007-LK in HER2-positive non-small cell lung cancer

  • Biochem Biophys Res Commun. 2024 Jun 11:725:150255. doi: 10.1016/j.bbrc.2024.150255.
Akari Shiraishi 1,  Tomoko Oh-Hara 2,  Yuki Takahashi 3,  Ken Uchibori 4,  Makoto Nishio 5,  Ryohei Katayama 6
Affiliations

Affiliations

  • 1 Div of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5, Kashiwanoha, Kashiwa-shi, Chiba, 277-8561, Japan.
  • 2 Div of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.
  • 3 Technical Research Institute, TOPPAN Holdings Inc., Japan; Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.
  • 4 Div of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan; Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 5 Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 6 Div of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5, Kashiwanoha, Kashiwa-shi, Chiba, 277-8561, Japan. Electronic address: ryohei.katayama@jfcr.or.jp.
PMID: 38897043 DOI: 10.1016/j.bbrc.2024.150255
Abstract

Human epidermal growth factor receptor 2 (HER2) aberrations are observed in various cancers. In non-small cell lung Cancer, genetic alterations activating HER2, mostly exon 20 insertion mutations, occur in approximately 2-4% of cases. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate has been approved as the first HER2-targeted drug for HER2-mutant lung Cancer. However, some cases are not responsive to T-DXd and the primary resistant mechanism remains unclear. In this study, we assessed sensitivity to T-DXd in JFCR-007, a patient-derived HER2-mutant lung Cancer cell line. Although JFCR-007 was sensitive to HER2 tyrosine kinase inhibitors, it showed resistance to T-DXd in attachment or spheroid conditions. Accordingly, we established a three-dimensional (3D) layered co-culture model of JFCR-007, where it exhibited a lumen-like structure and became sensitive to T-DXd. In addition, an in-house inhibitor library screening revealed that G007-LK, a tankyrase inhibitor, was effective when combined with T-DXd. G007-LK increased the cytotoxicity of topoisomerase-I inhibitor, DXd, a payload of T-DXd and SN-38. This combined effect was also observed in H2170, an HER2-amplified lung Cancer cell line. These results suggest that the proposed 3D co-culture system may help in evaluating the efficacy of T-DXd and may recapitulate the tumor microenvironment.

Keywords

3D co-culture system; G007-LK; HER2; NSCLC; Trastuzumab deruxtecan (T-DXd).

Figures
Products