PI-103, the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and
mammalian target of rapamycin (mTOR) shows high antitumor activity in
glioma xenografts. In the present study, clear antitumor activity was observed with
PI-103 treatment in two
gefitinib-resistant
non-small cell lung cancer (NSCLC) cell lines, A549 and H460, by simultaneously inhibiting
p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition. In addition, H460 cells with activating mutations of PIK3CA were more sensitive to
PI-103 than A549 cells with wild-type PIK3CA.
PI-103 was found to inhibit growth by causing G0-G1 arrest in A549 and H460 cells. Western blotting showed that
PI-103 induced down-regulation of
cyclin D1 and E1 and simultaneously up-regulated p21 and p27, associated with arrest in the G0-G1 phase of the cell cycle. Furthermore, p53, the
tumor suppressor which transcriptionally regulates p21, was also upregulated with
PI-103 treatment. Collectively, our results suggest that multitargeted intervention is the most effective
tumor therapy, and the cooperative blockade of PI3Kalpha and mTOR with
PI-103 shows promise for treating
gefitinib-resistant NSCLC.