Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTThe epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib-resistance and able to maintain pS6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.

Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human lung carcinomas

“…However, suppression of the mTOR signaling is not necessarily beneficial due to the presence of redundant negative feedback cascades [10,12]. Recently, primary and acquired resistance to EGFR-kinase inhibitors or mTOR inhibitors was observed in human tumors [12,24,34]. Based on these observations, cocktails of agents targeting multiple choke points have been proposed as more effective and may be better tolerated in the clinic due to the possibility of lower dosing [24].…”

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds

“…Moreover, combined inhibition using an mTOR inhibitor and anti-EGFR drugs was also found to be synergistic in selected NSCLC cells or patients in many other studies. Higher proliferation index or KRAS mutated status were included (24,25). In our study, the genetic status of PIK3CA was considered to illustrate the role of genetically distinct combined therapeutic interventions in EFGR-wild-type cells.…”

Clinical activity of mammalian target of rapamycin inhibitors in solid tumors

“…Synergistic antitumor effects have been observed when rapalogs are combined with multiple cytotoxics and targeted agents, as well as with radiation therapy [198][199][200]. For example, it has been published that lack of response to EGFR and HER2 inhibitors is associated with deregulation of downstream signaling elements and mTOR activation [201,202], and that this resistance could be bypassed by rapalogs [166,203]. Similarly, the ability of mTOR inhibitors to downregulate HIF and VEGF, and their demonstrated antiangiogenic effect makes the combination of these drugs and VEGFR inhibitors particularly interesting [67,204].…”

“…A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity [166].…”