Interestingly, two of our resistant cell lines demonstrated no basal PI3K/Akt activation, suggesting an alternative pathway to resistance. It is possible, how ever, that these resistant cell lines simply activated PI3K/ Akt in response to MAPK inhibition, as observed by Gopal et al. in melanoma cell lines. Conversely, selleck chemicals E6201 induced cell cycle arrest and cell death in some cell lines with constitutively active Akt, suggesting that although high pAkt does correlate with E6201 insensitiv ity, cell lines Inhibitors,Modulators,Libraries with high pAkt can still undergo a cytocidal response to E6201. Inhibitors,Modulators,Libraries None theless, our findings highlight the possible clinical utility of mutational and oncogenic pathway screening to strat ify patients to particular treatments.
PI3K inhibitors have previously been shown to be ef fective in melanoma cell lines not only in combination with MAPK inhibitors, but also in mono therapy. In a mouse model of cutaneous melanoma, Bedogni and colleagues demonstrated that com bined targeting of MAPK and PI3K significantly decreased tumour development and incidence more so than either agent given Inhibitors,Modulators,Libraries alone. Our findings confirm and expand on this previous work. We show that inhibition of the PI3K pathway in E6201 resistant cell lines with high levels of phosphorylated Akt can sensitize these cell lines to E6201. Indeed, synergy between the PI3K inhibi tor, LY294002, and E6201 was evident in all 6 cell lines tested, irrespective of PTEN mutation status, pAkt levels, or E6201 sensitivity. Interestingly, the greatest enhance ment of E6201 activity by LY294002 occurred in those cell lines that were resistant to E6201 alone.
On this note, multiple pharmaceutical companies are testing the effectiveness of combined MEK inhibition and PI3K or AKT inhibition in solid tumours including Inhibitors,Modulators,Libraries melanoma. There is also a Phase II trial testing the efficacy of the AZD6244 MEK inhibitor and MK 2206 AKT inhibitor in patients with relapsed BRAF V600E melanoma. Recent experience with vemurafenib has demonstrated that personalized cancer therapy can have a significant impact on patient response in this emerging era of mo lecularly targeted therapy. It is yet to be determined, however, whether MEK inhibitors can also impart mean ingful clinical benefits to melanoma patients.
To this end, recent preliminary results from a phase I clinical trial of the MEK1/2 inhibitor GSK1120212 in selected solid malignancies with a high frequency of BRAF muta tion were impressive with just under three quarters of BRAF Inhibitors,Modulators,Libraries mutant melanoma patients demon strating either a partial response selleck chemicals llc or stable disease with therapy. Furthermore, several phase I trials are currently assessing dual BRAF and MEK inhibition to target this oncogenic pathway at multiple levels. Conclusions MEK inhibitors are being extensively evaluated in melanoma patients both as single agents and in com bination with chemotherapy with thus far equivocal results.