1. Academic Validation
  2. Targeting epidermal growth factor receptor in paclitaxel-resistant human breast and lung cancer cells with upregulated glucose-6-phosphate dehydrogenase

Targeting epidermal growth factor receptor in paclitaxel-resistant human breast and lung cancer cells with upregulated glucose-6-phosphate dehydrogenase

  • Br J Cancer. 2022 Sep;127(4):661-674. doi: 10.1038/s41416-022-01843-1.
Hye-Young Min  # 1 Ho Jin Lee  # 1 Young-Ah Suh  # 2 Honglan Pei 1 Hyukjin Kwon 1 Hyun-Ji Jang 1 Hye Jeong Yun 1 Hyeong-Gon Moon 3 Ho-Young Lee 4
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
  • 3 Department of Surgery, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
  • 4 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea. hylee135@snu.ac.kr.
  • # Contributed equally.
Abstract

Background: Chemoresistance is a major obstacle to the successful treatment of triple-negative breast Cancer (TNBC) and non-small-cell lung Cancer (NSCLC). Therapeutic strategies to overcome chemoresistance are necessary to improve the prognosis of patients with these cancers.

Methods: Paclitaxel-resistant TNBC and NSCLC sublines were generated through continuous paclitaxel treatment over 6 months. The mechanistic investigation was conducted using MTT assay, LC/MS-based metabolite analysis, flow cytometry, western blot analysis, Real-Time PCR and tumour xenograft experiments.

Results: Glucose-6-phosphate dehydrogenase (G6PD) expression along with an increase in 3-phosphoglycerates and ribulose-5-phosphate production was upregulated in paclitaxel-resistant cells. Blockade of G6PD decreased viability of paclitaxel-resistant cells in vitro and the growth of paclitaxel-resistant MDA/R xenograft tumours in vivo. Mechanistically, activation of the epidermal growth factor receptor (EGFR)/Akt pathway mediates G6PD expression and G6PD-induced cell survival. Blockade of the EGFR pathway inhibited G6PD expression and sensitised those paclitaxel-resistant cells to paclitaxel treatment in vitro and in vivo. Analysis of publicly available datasets revealed an association between G6PD and unfavourable clinical outcomes in patients with breast or lung Cancer.

Conclusions: EGFR signaling-mediated G6PD expression plays a pivotal role in paclitaxel resistance, highlighting the potential of targeting EGFR to overcome paclitaxel resistance in TNBC and NSCLC cells overexpressing G6PD.

Figures
Products