TY - JOUR
T1 - The synergistic antitumor effect of combination therapy with a MEK inhibitor and YAP inhibitor on pERK-positive neuroblastoma
AU - Takemoto, Masakazu
AU - Tanaka, Tomoko
AU - Tsuji, Ryota
AU - Togashi, Yuichi
AU - Higashi, Mayumi
AU - Fumino, Shigehisa
AU - Tajiri, Tatsuro
N1 - Funding Information:
This work was supported by Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT KAKENHI grant number 20K08937 ) and by the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development , AMED (grant number 20ck0106609h0001). The English used in this manuscript was reviewed by Brian Quinn (Editor-in-Chief, Japan Medical Communication).
Publisher Copyright:
© 2021
PY - 2021/9/17
Y1 - 2021/9/17
N2 - Background: We previously reported the in vitro and in vivo antitumor effects of trametinib, a MEK inhibitor, on neuroblastoma with MAPK pathway mutations. As we observed eventual resistance to trametinib in our previous study, we evaluated the combination therapy of CA3, a YAP inhibitor, with trametinib, based on a recent report suggesting the potential involvement of YAP in the mechanism underlying the resistance to trametinib in neuroblastoma. Methods: SK-N-AS cells (a neuroblastoma cell line harboring RAS mutation) were treated with CA3 in vitro and subjected to a viability assay, immunocytochemistry and flow cytometry. Next, we analyzed the in vitro combination effect of CA3 and trametinib using the CompuSyn software program. Finally, we administered CA3, trametinib or both to SK-N-AS xenograft mice for 10 weeks to analyze the combination effect. Results: CA3 inhibited cell proliferation by both cell cycle arrest and apoptosis in vitro. Combination of CA3 and trametinib induced a significant synergistic effect in vitro (Combination Index <1). Regarding the in vivo experiment, combination therapy suppressed tumor growth, and 100% of mice in the combination therapy group survived, whereas the survival rates were 0% in the CA3 group and 33% in the trametinib group. However, despite this promising survival rate in the combination group, the tumors gradually grew after seven weeks with MAPK reactivation. Conclusion: Our results indicated that CA3 and trametinib exerted synergistic antitumor effects on neuroblastoma in vitro and in vivo, and CA3 may be a viable option for concomitant drug therapy with trametinib, since it suppressed the resistance to trametinib. However, this combination effect was not sufficient to achieve complete remission. Therefore, we need to adjust the protocol to obtain a better outcome by determining the mechanism underlying regrowth in the future.
AB - Background: We previously reported the in vitro and in vivo antitumor effects of trametinib, a MEK inhibitor, on neuroblastoma with MAPK pathway mutations. As we observed eventual resistance to trametinib in our previous study, we evaluated the combination therapy of CA3, a YAP inhibitor, with trametinib, based on a recent report suggesting the potential involvement of YAP in the mechanism underlying the resistance to trametinib in neuroblastoma. Methods: SK-N-AS cells (a neuroblastoma cell line harboring RAS mutation) were treated with CA3 in vitro and subjected to a viability assay, immunocytochemistry and flow cytometry. Next, we analyzed the in vitro combination effect of CA3 and trametinib using the CompuSyn software program. Finally, we administered CA3, trametinib or both to SK-N-AS xenograft mice for 10 weeks to analyze the combination effect. Results: CA3 inhibited cell proliferation by both cell cycle arrest and apoptosis in vitro. Combination of CA3 and trametinib induced a significant synergistic effect in vitro (Combination Index <1). Regarding the in vivo experiment, combination therapy suppressed tumor growth, and 100% of mice in the combination therapy group survived, whereas the survival rates were 0% in the CA3 group and 33% in the trametinib group. However, despite this promising survival rate in the combination group, the tumors gradually grew after seven weeks with MAPK reactivation. Conclusion: Our results indicated that CA3 and trametinib exerted synergistic antitumor effects on neuroblastoma in vitro and in vivo, and CA3 may be a viable option for concomitant drug therapy with trametinib, since it suppressed the resistance to trametinib. However, this combination effect was not sufficient to achieve complete remission. Therefore, we need to adjust the protocol to obtain a better outcome by determining the mechanism underlying regrowth in the future.
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U2 - 10.1016/j.bbrc.2021.07.028
DO - 10.1016/j.bbrc.2021.07.028
M3 - Article
C2 - 34271435
AN - SCOPUS:85109862705
VL - 570
SP - 41
EP - 46
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
ER -