Back to the drawing board

A significant limitation of genomically-guided targeted cancer therapies is the inevitability of innate or evolved resistance. Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous and anatomically complex cancer in which both the disease and available treatments carry considerable toxicity with lasting effects on patient quality of life; therapies with increased efficacy and decreased toxicity are needed. The therapeutic focus for HNSCC is shifting towards targeted inhibition of specific, frequently altered genes or pathways, including the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) network, which is the most frequently altered pathway in HNSCC. Agents targeting this network have demonstrated preclinical and clinical efficacy; however, as in most solid tumour malignancies, response to therapy is temporary and systems become refractory following prolonged treatment. In this review, I examine the role of emerged resistance with particular regard to targeted PI3K inhibitors in HNSCC and describe targetable mutations, pathway reactivation and bypass mechanisms as mediators of resistance. I conclude by emphasizing the value of combinatorial therapies and the value in re-evaluation of response to therapy over time to prevent or delay the onset of resistance. PI3K inhibitors and other targeted therapies have already begun transforming cancer care, providing improved patient responses and quality of life benefits. Characterizing resistance mechanisms will help guide the application of such agents, as well as the design of combination treatments to improve outcomes for cancer patients.