Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance. Therefore, the current work reviewed the role of PI3K/Akt pathway proteins, including Ras, PI3K, tumor suppressor phosphatase and tensing homolog, Akt and mammalian target of rapamycin in resistance to anti-EGFR treatment in HNSCC. In addition, we summarize PI3K/Akt pathway inhibitors that are currently under (pre)clinical investigation with focus on overcoming resistance to EGFR inhibitors. In conclusion, genomic alterations in and/or overexpression of one or more of these proteins are common in both human papillomavirus (HPV)-positive and HPV-negative HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising drug targets in the search for novel therapeutic strategies that are able to overcome resistance to anti-EGFR treatment. Co-targeting EGFR and the PI3K/Akt pathway can lead to synergistic drug interactions, possibly restoring sensitivity to EGFR inhibitors and hereby improving clinical efficacy. Better understanding of the predictive value of PI3K/Akt pathway alterations is needed to allow the identification of patient populations that might benefit most from these combination strategies.

中文翻译：

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PI3K/Akt 通路作为与 EGFR 靶向药物联合治疗头颈部鳞状细胞癌的有希望的治疗靶点的最新见解

对针对表皮生长因子受体 (EGFR) 的疗法（例如西妥昔单抗）的耐药性仍然是寻找头颈部鳞状细胞癌 (HNSCC) 有效治疗策略的主要障碍。由于其与 EGFR 途径的密切相互作用，已提出磷脂酰肌醇 3-激酶 (PI3K)/Akt 途径的多余或补偿性激活是对 EGFR 抑制剂耐药的主要驱动因素。了解参与该途径的每种主要蛋白质的作用对于开发能够规避耐药性的合理组合策略至关重要。因此，目前的工作回顾了 PI3K/Akt 通路蛋白，包括 Ras、PI3K、抑癌磷酸酶和张力同源物、Akt 和哺乳动物雷帕霉素靶点在 HNSCC 抗 EGFR 治疗中的作用。此外，我们总结了目前正在进行（前）临床研究的 PI3K/Akt 通路抑制剂，重点是克服对 EGFR 抑制剂的耐药性。总之，一种或多种这些蛋白质的基因组改变和/或过表达在人乳头瘤病毒 (HPV) 阳性和 HPV 阴性 HNSCC 肿瘤中都很常见。因此，PI3K/Akt 通路的下游效应物可作为有前景的药物靶点，用于寻找能够克服抗 EGFR 治疗耐药性的新治疗策略。共同靶向 EGFR 和 PI3K/Akt 途径可导致协同药物相互作用，可能恢复对 EGFR 抑制剂的敏感性，从而提高临床疗效。