Co-Targeting the EGFR and PI3K/Akt Pathway to Overcome Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma: What about Autophagy?

SIMPLE SUMMARY: Combining EGFR-targeted therapies, such as cetuximab, with a potent inhibitor of the PI3K/Akt pathway may be a novel therapeutic strategy that could potentially overcome/circumvent resistance. Interestingly, all pathways downstream of EGFR play a role in the regulation of the autophagic response and combining EGFR-targeted therapies with PI3K/Akt pathway inhibitors can therefore lead to therapy-induced autophagy. In this short commentary, we discuss that therapy-induced autophagy in these kind of combination strategies might not necessarily be a bad sign, as autophagy can also be a cell death mechanism. We highlight the fact that it remains challenging to elucidate the specific cellular requirements to promote autophagic cell death and illustrate this with recent literature. As autophagy also plays a role in anti-tumor immunity by ensuring the release of antigens, potentially leading to recognition and elimination of the tumor, we believe that it is worth investigating autophagy as an anti-tumor mechanism in HNSCC. ABSTRACT: Resistance to EGFR-targeted therapy is a major obstacle on the road to effective treatment options for head and neck cancers. During the search for underlying mechanisms and regulators of this resistance, there were several indications that EGFR-targeted therapy resistance is (partially) mediated by aberrant signaling of the PI3K/Akt pathway. Genomic alterations in and/or overexpression of major components of the PI3K/Akt pathway are common in HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising targets in the search for novel therapeutic strategies overcoming resistance to EGFR inhibitors. As both the EGFR/Ras/Raf/MAPK and the PI3K/Akt pathway are involved in autophagy, combinations of EGFR and PI3K/Akt pathway inhibitors can induce an autophagic response in tumor cells. This activation of autophagy can be seen as a “double-edge sword”, depending on the cellular context. Autophagy is largely known as a cytoprotective mechanism, but it can also be a mechanism of programmed (autophagic) cell death. The activation of autophagy during anti-cancer treatment is, therefore, not necessarily a bad sign. However, in HNSCC, the role of therapy-induced autophagy as an anti-tumor mechanism is still largely unclear. Further research is warranted to understand the potential of combination treatments targeting both the EGFR and PI3K/Akt pathway.