1.MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma.
Mohan S1, Vander Broek R1, Shah S2, Eytan DF1, Pierce ML3, Carlson SG2, Coupar JF2, Zhang J2, Cheng H2, Chen Z4, Van Waes C4. Clin Cancer Res. 2015 Sep 1;21(17):3946-56. doi: 10.1158/1078-0432.CCR-14-3377. Epub 2015 May 14.
PURPOSE: Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined.
2.Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts.
Andersen NJ1, Boguslawski EB1, Kuk CY1, Chambers CM2, Duesbery NS1. Int J Oncol. 2015 Jul;47(1):71-80. doi: 10.3892/ijo.2015.2989. Epub 2015 May 6.
Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. Using tumorgraft models, we previously showed that AS is sensitive to small-molecule inhibitors that target mitogen-activated/extracellular-signal-regulated protein kinase kinases 1 and 2 (MEK). The objective of this study was to identify drugs that combine with MEK inhibitors to more effectively inhibit AS growth. We examined the in vitro synergy between the MEK inhibitor PD0325901 and inhibitors of eleven common cancer pathways in melanoma cell lines and canine angiosarcoma cell isolates. Combination indices were calculated using the Chou-Talalay method. Optimized combination therapies were evaluated in vivo for toxicity and efficacy using canine angiosarcoma tumorgrafts. Among the drugs we tested, rapamycin stood out because it showed strong synergy with PD0325901 at nanomolar concentrations. We observed that angiosarcomas are insensitive to mTOR inhibition.
3.Application Of Small Molecules Favoring Naïve Pluripotency during Human Embryonic Stem Cell Derivation.
Van der Jeught M1,2, Taelman J1,2, Duggal G1, Ghimire S1, Lierman S1, Chuva de Sousa Lopes SM1,3, Deforce D4, Deroo T1, De Sutter P1, Heindryckx B1. Cell Reprogram. 2015 Jun;17(3):170-80. doi: 10.1089/cell.2014.0085.
In mice, inhibition of both the fibroblast growth factor (FGF) mitogen-activated protein kinase kinase/extracellular-signal regulated kinase (MEK/Erk) and the Wnt signaling inhibitor glycogen synthase-3β (GSK3β) enables the derivation of mouse embryonic stem cells (mESCs) from nonpermissive strains in the presence of leukemia inhibitory factor (LIF). Whereas mESCs are in an uncommitted naïve state, human embryonic stem cells (hESCs) represent a more advanced state, denoted as primed pluripotency. This burdens hESCs with a series of characteristics, which, in contrast to naïve ESCs, makes them not ideal for key applications such as cell-based clinical therapies and human disease modeling. In this study, different small molecule combinations were applied during human ESC derivation. Hereby, we aimed to sustain the naïve pluripotent state, by interfering with various key signaling pathways. First, we tested several combinations on existing, 2i (PD0325901 and CHIR99021)-derived mESCs.
4.Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.
Stewart A1, Thavasu P1, de Bono JS2, Banerji U3. Ann Oncol. 2015 Jul;26(7):1504-10. doi: 10.1093/annonc/mdv188. Epub 2015 Apr 23.
BACKGROUND: We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents.
