Head and Neck Cancer Research Team, Cancer Research Malaysia, No. 1, Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
Department of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
Sci Rep. 2019 Feb 20;9(1):2357. doi: 10.1038/s41598-019-38742-0.
The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted.
表皮生长因子受体抑制剂（EGFRIs）单独用于口腔鳞状细胞癌（OSCC）的治疗效果有限，因此需要寻找能够预测哪些患者亚组可能受益的生物标志物。在这里，我们确定了厄洛替尼在 OSCC 细胞系中的疗效，并通过比较敏感和耐药细胞系来确定潜在的生物标志物。我们重点研究了周围蛋白（PPL）中的 4717C>G 多态性，CC 基因型与厄洛替尼耐药相关。为了验证这一点，我们构建了携带 CC 基因型的厄洛替尼耐药细胞系，使其过表达 GG 基因型，反之亦然。然后研究了这些同源细胞系对厄洛替尼治疗的反应。我们证明，在厄洛替尼耐药细胞系中过表达 GG 基因型可使其对厄洛替尼敏感，并抑制 AKT 磷酸化。同样，CC 基因型的表达赋予了对厄洛替尼的耐药性，同时 AKT 磷酸化增加。我们还表明，与 GG 基因型相比，CC 基因型的细胞系通常对其他 EGFR 抑制剂更耐药。总的来说，我们表明 PPL 基因中的特定多态性可导致对厄洛替尼和其他 EGFR 抑制剂的耐药性，进一步评估这些作为反应生物标志物的工作是必要的。
