The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models

Abstract

Background:Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance.Methods:Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo.Results:Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival.Conclusions:Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness.

Treatment effect of buparlisib, cetuximab and irradiation in wild-type or PI3KCA-mutated head and neck cancer cell lines

“…We observed that in both cell lines cetuximab given alone exerted antiproliferative effect only at high concentrations (>10 −4 M, Figs. 1b and 2), as confirmed by recent studies in different HNSCC cell lines [17]. Moreover, we noted that sequence 2 was the best treatment in both cell lines.…”

“…However, in PI3KCA wild-type cells, we observed a possible activation of mTORC2 complex, not seen in mutated cells where p-p70 up-regulation probably determined the suppression of mTORC2 activity. Thus, it would be a great interest to test the combination of a dual PI3K/mTOR inhibitor and anti-EGFR therapy in head and neck cancer [17]. Intriguingly, our data showed that the same two drugs given in the opposite order (buparlisib followed by cetuximab, sequence 1) resulted in an antagonistic effect, as demonstrated by a CI>1.…”

“…We have previously shown that mTOR inhibition enhances the antitumor activity of the cetuximab-bevacizumab-irradiation combination on head and neck cancer xenografts [16]. A dual PI3K/mTOR inhibitor (PKI-587) has been proved to restore sensitivity to cetuximab in cells resistant to it [17].…”

Radiation Enhancement of Head and Neck Squamous Cell Carcinoma by the Dual PI3K/mTOR Inhibitor PF-05212384

“…Experimental evidence has surfaced indicating PF-05212384 dual PI3K/mTOR inhibition rescues HNSCC from cetuximab resistance (47). The ability to re-sensitize tumor cells previously resistant to a known radiosensitizing agent indicates PF-05212384, a significant radiosensitizing agent solely by itself, could potentially be quite efficacious for the treatment of cetuximab resistant HNSCC.…”

Synthesis and in vitro evaluation of 4-substituted furano[3,2-c] tetrahydroquinolines as potential anti-cancer agents

“…Due to their structural novelty and important biological activities, the synthesis of complex chiral molecules around a biologically relevant framework has played an important role in the discovery of drugs 14 . Furthermore, some 2-phenylbenzofuran analogues have showed potent anticancer activities [15][16][17] . The [4 + 2] cycloaddition between N-arylimines and electron-rich alkenes, the multicomponent Povarov reaction has been catalyzed by various lewis acid catalysts, such as I 2 , InCl 3 , TFA and p-TsOH [18][19][20][21][22] .…”