Additional study is required to determine whether SMPD3 overexpression helps to sustain EGFR signaling following treatment with erlotinib, whether this sustained signaling is responsible for reduced erlotinib sensitivity in SMPD3+ cell lines, and whether the limited efficacy of erlotinib in clinical trials of head and neck squamous cell carcinoma may be mediated in part by nSMase2 activation [41–43]. Here, SMPD3 is linked to head and neck squamous cell carcinoma.