Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors

被引:31
作者
Aasen, Synnove Nymark [1 ,2 ]
Parajuli, Himalaya [1 ]
Tuyen Hoang [1 ]
Feng, Zichao [1 ,3 ]
Stokke, Krister [1 ]
Wang, Jiwei [1 ,3 ]
Roy, Kislay [1 ]
Bjerkvig, Rolf [1 ,4 ]
Knappskog, Stian [2 ,5 ]
Thorsen, Frits [1 ,4 ,6 ]
机构
[1] Univ Bergen, Kristian Gerhard Jebsen Brain Tumour Res Ctr, Dept Biomed, Jonas Lies Vei 91, N-5009 Bergen, Norway
[2] Haukeland Hosp, Dept Oncol & Med Phys, Jonas Lies Vei 65, N-5021 Bergen, Norway
[3] Shandong Univ, Brain Sci Res Inst, 44 Wenhuaxi Rd, Jinan 250100, Shandong, Peoples R China
[4] Luxembourg Inst Hlth, Dept Oncol, NorLux Neurooncol Lab, 84 Val Fleuri, L-1526 Luxembourg, Luxembourg
[5] Univ Bergen, Sect Oncol, Dept Clin Sci, N-5020 Bergen, Norway
[6] Univ Bergen, Dept Biomed, Mol Imaging Ctr, Jonas Lies Vei 91, N-5009 Bergen, Norway
关键词
melanoma; brain metastasis; BRAF; MAPK; PI3K; combined treatment; apoptosis; CANCER CELLS; ACQUIRED-RESISTANCE; BUPARLISIB BKM120; BRAIN METASTASIS; DOSE-ESCALATION; IN-VITRO; MEK; APOPTOSIS; EXPRESSION; SURVIVIN;
D O I
10.3390/ijms20174235
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.
引用
收藏
页数:19
相关论文
共 60 条
[1]   The biology and therapeutic management of melanoma brain metastases [J].
Abate-Daga, Daniel ;
Ramello, Maria C. ;
Smalley, Inna ;
Forsyth, Peter A. ;
Smalley, Keiran S. M. .
BIOCHEMICAL PHARMACOLOGY, 2018, 153 :35-45
[2]   Signatures of mutational processes in human cancer [J].
Alexandrov, Ludmil B. ;
Nik-Zainal, Serena ;
Wedge, David C. ;
Aparicio, Samuel A. J. R. ;
Behjati, Sam ;
Biankin, Andrew V. ;
Bignell, Graham R. ;
Bolli, Niccolo ;
Borg, Ake ;
Borresen-Dale, Anne-Lise ;
Boyault, Sandrine ;
Burkhardt, Birgit ;
Butler, Adam P. ;
Caldas, Carlos ;
Davies, Helen R. ;
Desmedt, Christine ;
Eils, Roland ;
Eyfjord, Jorunn Erla ;
Foekens, John A. ;
Greaves, Mel ;
Hosoda, Fumie ;
Hutter, Barbara ;
Ilicic, Tomislav ;
Imbeaud, Sandrine ;
Imielinsk, Marcin ;
Jaeger, Natalie ;
Jones, David T. W. ;
Jones, David ;
Knappskog, Stian ;
Kool, Marcel ;
Lakhani, Sunil R. ;
Lopez-Otin, Carlos ;
Martin, Sancha ;
Munshi, Nikhil C. ;
Nakamura, Hiromi ;
Northcott, Paul A. ;
Pajic, Marina ;
Papaemmanuil, Elli ;
Paradiso, Angelo ;
Pearson, John V. ;
Puente, Xose S. ;
Raine, Keiran ;
Ramakrishna, Manasa ;
Richardson, Andrea L. ;
Richter, Julia ;
Rosenstiel, Philip ;
Schlesner, Matthias ;
Schumacher, Ton N. ;
Span, Paul N. ;
Teague, Jon W. .
NATURE, 2013, 500 (7463) :415-+
[3]   Opinion - Survivin, cancer networks and pathway-directed drug discovery [J].
Altieri, Dario C. .
NATURE REVIEWS CANCER, 2008, 8 (01) :61-70
[4]   Phase I dose- escalation study of buparlisib ( BKM120), an oral pan- class I PI3K inhibitor, in Japanese patients with advanced solid tumors [J].
Ando, Yuichi ;
Inada-Inoue, Megumi ;
Mitsuma, Ayako ;
Yoshino, Takayuki ;
Ohtsu, Atsushi ;
Suenaga, Naoko ;
Sato, Masahiko ;
Kakizume, Tomoyuki ;
Robson, Matthew ;
Quadt, Cornelia ;
Doi, Toshihiko .
CANCER SCIENCE, 2014, 105 (03) :347-353
[5]   A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors [J].
Bedard, Philippe L. ;
Tabernero, Josep ;
Janku, Filip ;
Wainberg, Zev A. ;
Paz-Ares, Luis ;
Vansteenkiste, Johan ;
Van Cutsem, Eric ;
Perez-Garcia, Jose ;
Stathis, Anastasios ;
Britten, Carolyn D. ;
Le, Ngocdiep ;
Carter, Kirsten ;
Demanse, David ;
Csonka, Denes ;
Peters, Malte ;
Zubel, Angela ;
Nauwelaerts, Heidi ;
Sessa, Cristiana .
CLINICAL CANCER RESEARCH, 2015, 21 (04) :730-738
[6]   New developments in brain metastases [J].
Berghoff, Anna S. ;
Preusser, Matthias .
THERAPEUTIC ADVANCES IN NEUROLOGICAL DISORDERS, 2018, 11
[7]   Influence of p53 Isoform Expression on Survival in High-Grade Serous Ovarian Cancers [J].
Bischof, Katharina ;
Knappskog, Stian ;
Hjelle, Sigrun M. ;
Stefansson, Ingunn ;
Woie, Kathrine ;
Salvesen, Helga B. ;
Gjertsen, Bjorn T. ;
Bjorge, Line .
SCIENTIFIC REPORTS, 2019, 9 (1)
[8]   Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer [J].
Bissig-Choisat, Beatrice ;
Kettlun-Leyton, Claudia ;
Legras, Xavier D. ;
Zorman, Barry ;
Barzi, Mercedes ;
Chen, Leon L. ;
Amin, Mansi D. ;
Huang, Yung-Hsin ;
Pautler, Robia G. ;
Hampton, Oliver A. ;
Prakash, Masand M. ;
Yang, Diane ;
Borowiak, Malgorzata ;
Muzny, Donna ;
Doddapaneni, Harsha Vardhan ;
Hu, Jianhong ;
Shi, Yan ;
Gaber, M. Waleed ;
Hicks, M. John ;
Thompson, Patrick A. ;
Lu, Yiling ;
Mills, Gordon B. ;
Finegold, Milton ;
Goss, John A. ;
Parsons, D. Williams ;
Vasudevan, Sanjeev A. ;
Sumazin, Pavel ;
Lopez-Terrada, Dolores ;
Bissig, Karl-Dimiter .
JOURNAL OF HEPATOLOGY, 2016, 65 (02) :325-333
[9]  
Boucher MJ, 2000, J CELL BIOCHEM, V79, P355, DOI 10.1002/1097-4644(20001201)79:3<355::AID-JCB20>3.0.CO
[10]  
2-0