However, there have been issues with the tolerability of the combination treatment in two phase 1b trials combining the MEK inhibitor trametinib, with either the pan-PI3K inhibitor buparlisib, or the PI3K/mTOR inhibitor GSK2126458, where the former study showed promising anti-tumour activity but frequent dose interruptions and reductions were necessary due to toxicity [54]. This evidence concerns the gene MTOR and neoplasm.