We want to thank Liang (2021) for his comments on using afatinib and palbociclib as a combination treatment for head and neck cancer. The author has raised the question regarding the effectiveness of combining afatinib with palbociclib to treat HNSCC [1]. To date, various studies have shown the preclinical and clinical activity of afatinib alone or in combination with other chemotherapeutic agents or radiation therapy [2–6]. A recent clinical trial (NCT01345682) by Haddad et al. (2019) with afatinib as a second-line therapy has shown improvement in the progression-free survival of HNSCC patients with recurrent/metastatic disease [7]. Note that such clinical advantage was demonstrated on patients that have progressed from platinum-based therapy with little-to-no other effective treatment options [7]. Our previous study with afatinib as a radiosensitizer have indicated a reduction in the tumor growth and cancer stem cell population in HNSCC [6].
As indicated in our manuscript [1], xenografts that were nonresponsive to the treatments demonstrated a dramatic increase in the cyclin D1, CDK4/6, and activated form of EGFR, suggesting the existence of a by-passing mechanism for tumor cell survival. Additionally, treatment with palbociclib alone too can lead to the activation of EGFR signaling in HNSCC cells suggesting the need to target EGFR and CDK4/6 signaling to prevent tumor cells from using alternative pathways for its survival and growth. The effectiveness of this combination can be observed in the synergy score estimate with both the drugs (afatinib and palbociclib) that have shown an additive effect in HNSCC cells which signifies the clinical importance of the combination.
mTOR/Ribosomal protein S6 signaling is associated with cellular metabolism, cell size, and protein synthesis. Phosphorylated S6 may also predict therapy response in cancer [8, 9]. Similarly, there was an increased pS6 expression in HNSCC tumors and cell lines (two to three-fold) during treatment with palbociclib as a monotherapy which can be abrogated when treated in combination with afatinib [1]. Although treatment with afatinib or palbociclib as a monotherapy showed a decrease in tumor volume and tumor weight as evident in Ki67 expression, the use of alternative bypassing survival mechanism by the cancer cells cannot be eliminated [1]. Under such condition, combination therapy with afatinib with palbociclib present a better therapeutic option to restrict the tumor cells from using alterative survival mechanisms in HNSCC.
Footnotes
Conflict of interest
SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. AKG has received consulting fees from AstraZeneca, Jazz Pharmaceuticals, G1 Therapeutics, Blueprint Medicines, Genentech, Flagship Biosciences, Mirati Therapeutics and research support form Takeda. AKG also serves on a DSMC for YMAbs. Other authors declare no potential conflicts of interest.
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