Sci Transl Med

Sci Transl Med. MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long\term treatment with the combination therapy induced the conversion from EMT to mesenchymal\to\epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR\TKI. In conclusion, our results indicate that this combined therapy using MEK and PI3K inhibitors is usually a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR\TKIs. mutations, representing a breakthrough in the treatment of NSCLC patients.1, 2 However, NSCLC patients initially showing response to EGFR\TKI treatment often eventually acquire resistance to TKIs, resulting in relapse and cancer\related death. A number of diverse mechanisms have been shown to underlie the development of acquired resistance to EGFR\TKIs in NSCLC, which makes it difficult to overcome the drug resistance to EGFR\TKIs. Starting with the report of the appearance of a Gemfibrozil (Lopid) secondary T790M mutation in 2005, numerous resistance mechanisms have been reported by our group and others, such as amplification, activation of the mesenchymal\epithelial transition factor/hepatocyte growth factor axis, induction of epithelial\to\mesenchymal transition (EMT), acquisition of stem cell properties, and transformation from NSCLC into small cell lung cancer.3, 4, 5, 6, 7, 8 Recently, osimertinib, a third\generation EGFR\TKI, was developed to Gemfibrozil (Lopid) overcome the resistance associated with the T790M mutation, and is expected to play an important role in the treatment of advanced NSCLC.9 However, the emergence of resistance to osimertinib by various mechanisms, including the appearance of the C797S mutation, has already become a serious problem.10, 11, 12 These phenomena Gemfibrozil (Lopid) demand the development of novel therapeutic strategies for advanced NSCLC with acquired resistance to EGFR\TKIs. In attempting to overcome acquired resistance to EGFR\TKIs caused by receptor tyrosine kinase Rabbit Polyclonal to STK24 (RTK)\targeted therapy, the downstream pathways could be viewed as affordable next targets. The emergence of the T790M mutation is known to lead to reactivation of the MEK/ERK or PI3K/AKT pathway.13, 14, 15 Several studies have also demonstrated that amplification promotes resistance to TKIs by reactivating both the PI3K/AKT and MEK/ERK pathways.4, 16 Thus, most of the resistance mechanisms were associated with unexpected aberrant re\awakening of the key intracellular signals that were basically inhibited by the TKIs. However, although these pathways are attractive therapeutic targets, it is well Gemfibrozil (Lopid) known that this inhibition of one pathway can lead to compensatory activation of the other pathway, which leads to diminished efficacy of single\agent therapies,17 and overcoming the feedback loop is one of the major issues for molecular targeted therapy in many types of cancer. Among such intrinsic mutual compensation systems of intracellular signal transduction networks in cancer, the tight relationship between MEK/ERK and PI3K/AKT pathways has been of particular interest.18, 19, 20, 21 Indeed, there are reports describing the efficacy of combined inhibition of MEK and PI3K signaling in several types of cancers.22, 23, 24, 25 Furthermore, several clinical trials evaluating the feasibility of MEK plus PI3K dual blockade therapy for advanced solid tumors are currently ongoing.26 A recent search on (, accessed on June 30, 2018) yielded 10 clinical trials for investigating the efficacy of the combined use of MEK and PI3k inhibitors. Among them, 2 trials Gemfibrozil (Lopid) for patients with solid tumors were terminated due to the lack of tolerability, suggesting the necessity for further consideration of it in some issues, such as knowing the treatment indication, optimal types of MEK and PI3K inhibitors and their doses to be used at not only clinical settings but also basic in?vitro contexts. To the best of our.