Cellular metabolism is substantially altered during tumor progression, and associated with poor prognosis and therapeutic resistance of human cancers. Therefore, the metabolic rewiring of cancer cells has been viewed as a promising source for novel drug targets, and being actively pursued in the development of selective antineoplastic agents. EGFR targeted agents currently approved or under investigation for head and neck squamous cell carcinoma (HNSCC) include EGFR monoclonal antibodies or EGFR tyrosine kinase inhibitors (EGFR-TKI). However, HNSCC patients failing to these agents treatment, due to the development of acquired tumor resistance, will have a compromised survival. We have identified a novel EGFR-TKI, BPR3K007S0. Based on the EC50 in enzyme-based assay of wild-type EGFR & EGFR mutant L858R protein, BPR3K007S0 is more effective than that of clinical used EGFR-TKI gefitinib (Iressa). We further evaluated the drug effects on EGFR phosphorylation in HNSCC cells, and found that BPR3K007S0 inhibited phosphorylation of EGFR in a time-dependent manner. Further study demonstrated that BPR3K007S0 decreased HNSCC cell proliferation and colony formation by causing G1-phase arrest, which was strongly associated with a marked decrease of the level of cyclin E and cdk2 with concomitant induction of p21 and p27. Notably, BPR3K007S0 showed much potent effect toward cell growth in vitro and in vivo than that of gefitinib in HNSCC cells, implicating that the anticancer effect of BPR3K007S0 is not limited to EGFR inhibition. More importantly, we found that BPR3K007S0 significantly suppressed the expression of a wide range of metabolic genes. Among them, the levels of c-Myc and hexokinase 2 were significantly decreased in a time-dependent manner by treatment with BPR3K007S0. Gene manipulation study demonstrated that knockdown of c-Myc leads to a decreased level of hexokinase 2. In this system, silence of EGFR did not affect c-Myc expression, suggesting that c-Myc may not be the EGFR downstream target in used HNSCC cells. Taken together, these results revealed that BPR3K007S0 has added benefits by targeting of EGFR and cancer metabolism, and are likely to be superior to gefitinib in HNSCC models. Thus, development of multi-kinase and metabolic inhibitors holds promises for overcoming treatment resistance of HNSCC. (Grant support: DOH102-TD-M-111-102001)

Citation Format: Ching-Chuan Kuo, Hsing-Pang Hsieh, Hsing-Jien Kung. Targeting tumor metabolism by novel EGFR inhibitor in head and neck cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A171.