| Reference | 1. Anticancer Res. 2017 Jun;37(6):2831-2838. <br />
MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in
KRAS-mutated Human Colorectal Cancer Cell Lines. <br />
Gong J(1), Chen Y(2), Yang L(3), Pillai R(3), Shirasawa S(4), Fakih M(5). <br />
Author information: <br />
(1)Department of Medical Oncology, City of Hope National Medical Center, Duarte,
CA, U.S.A.
(2)Department of Molecular Medicine, City of Hope National Medical Center,
Duarte, CA, U.S.A.
(3)Department of Pathology, City of Hope National Medical Center, Duarte, CA,
U.S.A.
(4)Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka,
Japan.
(5)Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive
Cancer Center, Duarte, CA, U.S.A. [email protected]. <br />
BACKGROUND: Preclinical evidence demonstrates that mitogen-activated protein
kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway
inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer
(CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell
sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and
proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are
common in CRC and often lead to resistance to chemotherapy.
MATERIALS AND METHODS: Wild-type and mutant KRAS/BRAF human CRC cell lines were
treated with escalating doses of 5-FU or trifluridine with MEK162 (MEK1/2
inhibitor) for 72 h. Cell viability was assessed by
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and synergism
expressed by the combination index was calculated using CalcuSyn.
RESULTS: Evidence of synergistic antitumor activity was observed for the majority
of human CRC cell lines treated with MEK162 plus 5-FU (4/6) or trifluridine
(7/9). Synergism was greater in KRAS- or BRAF-mutant cell lines compared to
wild-type KRAS/BRAF CRC cell lines.
CONCLUSION: The combination of MEK inhibition and trifluridine is worthwhile
advancing in clinical development, particularly for treatment-refractory KRAS- or
BRAF-mutated metastatic CRC. <br />
2. Cancer Lett. 2015 Aug 1;364(1):70-8. doi: 10.1016/j.canlet.2015.04.028. Epub 2015
Apr 29. <br />
Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking
autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells. <br />
Yao W(1), Yue P(2), Zhang G(2), Owonikoko TK(2), Khuri FR(2), Sun SY(3). <br />
Author information: <br />
(1)Department of Respiration, Xiangya Hospital and Xiangya School of Medicine,
Central South University, Changsha, Hunan, China; Department of Hematology and
Medical Oncology, Emory University School of Medicine and Winship Cancer
Institute, Atlanta, GA, USA.
(2)Department of Hematology and Medical Oncology, Emory University School of
Medicine and Winship Cancer Institute, Atlanta, GA, USA.
(3)Department of Hematology and Medical Oncology, Emory University School of
Medicine and Winship Cancer Institute, Atlanta, GA, USA. Electronic address:
[email protected]. <br />
Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due
to a high frequency of K-Ras mutation and is thus a potential candidate for
MEK-targeted therapy. The current study focuses on demonstrating the activity of
MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and
exploring possible mechanism-driven strategies to enhance its therapeutic
efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied
potencies through induction of G1 cell cycle arrest and apoptosis. Moreover, it
induces autophagy and accordingly the combination of MEK162 with the autophagy
inhibitor, chloroquine, synergistically inhibits the growth of NSCLC cells and
enhances apoptosis. MEK162 activates Akt signaling while effectively inhibiting
MEK/ERK signaling. Accordingly, the combination of MEK162 and BKM120
(buparlisib), a pan-PI3K inhibitor, abrogates induced Akt activation and
significantly augments therapeutic efficacy against the growth of NSCLC cells
both in vitro and in vivo. Hence our findings warrant further evaluation of these
rational combinations in the clinic. <br />
3. Lancet Oncol. 2013 Mar;14(3):249-56. doi: 10.1016/S1470-2045(13)70024-X. Epub
2013 Feb 13. <br />
MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF
mutations: a non-randomised, open-label phase 2 study. <br />
Ascierto PA(1), Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P,
Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel
A, Dummer R. <br />
Author information: <br />
(1)National Tumor Institute, Foundation G Pascale, Naples, Italy. <br />
BACKGROUND: Patients with melanoma harbouring Val600 BRAF mutations benefit from
treatment with BRAF inhibitors. However, no targeted treatments exist for
patients with BRAF wild-type tumours, including those with NRAS mutations. We
aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients
with NRAS-mutated or Val600 BRAF-mutated advanced melanoma.
METHODS: In our open-label, non-randomised, phase 2 study, we assigned patients
with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment
arms on the basis of mutation status. Patients were enrolled at university
hospitals or private cancer centres in Europe and the USA. The three arms were:
twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for
BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma.
Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor
therapy was not allowed. The primary endpoint was the proportion of patients who
had an objective response (ie, a complete response or confirmed partial
response). We report data for the 45 mg groups. We assessed clinical activity in
all patients who received at least one dose of MEK162 and in patients assessable
for response (with two available CT scans). This study is registered with
ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional
patients with NRAS mutations (based on a protocol amendment).
FINDINGS: Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who
received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median
follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete
response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial
response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated
melanoma (two confirmed). The most frequent adverse events were acneiform
dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients
with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema
(ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea
(eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and
nine [22%]). Increased creatine phosphokinase was the most common grade 3-4
adverse event (seven [23%] and seven [17%]). Four patients had serious adverse
events (two per arm), which included diarrhoea, dehydration, acneiform
dermatitis, general physical deterioration, irregular heart rate, malaise, and
small intestinal perforation. No deaths occurred from treatment-related causes.
INTERPRETATION: To our knowledge, MEK162 is the first targeted therapy to show
activity in patients with NRAS -mutated melanoma and might offer a new option for
a cancer with few effective treatments.
FUNDING: Novartis Pharmaceuticals. <br />
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