Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma
Haiquan Lu, Yang Lu, Yangyiran Xie, Songbo Qiu, Xinqun Li, Zhen Fan
Haiquan Lu, Yang Lu, Yangyiran Xie, Songbo Qiu, Xinqun Li, Zhen Fan
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Research Article Metabolism Therapeutics

Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma

Abstract

Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.

Authors

Haiquan Lu, Yang Lu, Yangyiran Xie, Songbo Qiu, Xinqun Li, Zhen Fan

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Figure 7

Cetuximab plus PDK1 inhibition induces apoptosis in HNSCC cells with acquired resistance to cetuximab and inhibits their growth in vivo when used in combination with DCA.

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Cetuximab plus PDK1 inhibition induces apoptosis in HNSCC cells with acq...
(A) Left, established HN5 xenografts (~250 mm3) were untreated or treated with cetuximab (0.25 mg/mouse, twice a week for 3 weeks). Right, HN5-R xenografts (~250 mm3) were untreated or treated with the same dose of cetuximab, DCA (50 or 250 mg/kg/day), or DCA plus cetuximab for 3 weeks. (B) Established FaDu (upper) and FaDu-R (lower) xenografts (~250 mm3) were untreated or treated as described in A for HN5-R xenografts. After completion of treatments, the mice were subjected to IVIS imaging and then observed for additional days for tumor progression or regression. The recording of tumor sizes was stopped when fewer than 4 mice remained in any group because of sacrifice of mice with large tumor burden or morbid or moribund status. (C) Established UMSCC1 xenografts (~150 mm3) were untreated or treated with cetuximab (0.25 mg/mouse, twice a week for 3 weeks), DCA (50 or 250 mg/kg/day), or DCA plus cetuximab for 3 weeks. After completion of treatments on day 21, the mice were subjected to IVIS imaging and then observed for additional days for tumor progression or regression. The recording of tumor sizes was stopped when fewer than 4 mice remained in any group because of sacrifice of mice with large tumor burden or morbid or moribund status. Error bars indicate ± SEM. Rx, treatment.