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Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR‐targeting agents to treat head and neck squamous cell carcinoma
Author(s) -
Zaryouh Hannah,
De Pauw Ines,
Baysal Hasan,
Peeters Marc,
Vermorken Jan Baptist,
Lardon Filip,
Wouters An
Publication year - 2022
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.21806
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , cetuximab , head and neck squamous cell carcinoma , cancer research , egfr inhibitors , epidermal growth factor receptor , medicine , pten , biology , signal transduction , cancer , head and neck cancer , microbiology and biotechnology , colorectal cancer
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.