mTOR Cotargeting Active in Cetuximab-Resistant Head/Neck Cancers With PIK3CA and RAS Mutations

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In a study reported in Journal of the National Cancer Institute, Wang and colleagues found that adding an mTOR inhibitor to cetuximab (Erbitux) resulted in marked improvement in antitumor activity in squamous cell carcinomas of the head and neck expressing PIK3CA and RAS oncogenes.

Cetuximab treatment of PIK3CA- and RAS-expressing squamous cell head and neck carcinoma mouse xenografts resulted in initial tumor response followed by relapse within a few weeks. It was found that cetuximab did not reduce the activity of mTOR (a downstream signaling target of EGFR, PIK3CA, and RAS) in these tumors. The addition of an mTOR inhibitor to cetuximab produced markedly greater antitumor activity, particularly in the head and neck cancer cells resistant to cetuximab as a single agent; combined treatment produced prompt tumor collapse of both PIK3CA- and RAS-expressing head and neck carcinoma xenografts (P < .001), together with significant reductions in proliferation (P < .001) and lymphangiogenesis (P < .001).

The investigators concluded: “The presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in [squamous cell carcinomas of the head and neck] could be exploited to predict potential resistance to cetuximab and to select the patients who may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for [patients with squamous cell carcinoma of the head and neck].” ■

Wang Z, et al: J Natl Cancer Inst 106(9):dju215, 2014.




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