RT Journal Article
SR Electronic
T1 Inhibition of MEK alone and in combination with ALK inhibition suppresses tumor growth in a mouse model of ALK positive lung cancer.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.120.266049
DO 10.1124/jpet.120.266049
A1 Nensi Shrestha
A1 Abigail R Bland
A1 Rebecca L Bower
A1 Rhonda Rosengren
A1 John Ashton
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/04/13/jpet.120.266049.abstract
AB Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer most commonly arises through EML4-ALK chromosomal fusion. We have previously demonstrated that combination of the ALK inhibitor crizotinib with the MEK inhibitor selumetinib was highly effective at reducing cell viability of ALK-positive NSCLC (H3122) cells. In this study, we further investigated the efficacy of crizotinib and selumetinib combination therapy in an in vivo xenograft model of ALK-positive lung cancer. Crizotinib decreased tumor volume by 52% compared to control, and the drug combination reduced tumor growth compared to crizotinib. In addition, MEK inhibition alone reduced tumor growth by 59% compared to control. Crizotinib, selumetinib, alone and in combination were non-toxic at the dose of 25 mg/kg with values for ALT (< 80 U/L) and creatinine (<2 mg/dL) within the normal range. Our results support the combined use of crizotinib with selumetinib in ALK-positive lung cancer but raise the possibility that a sufficient dose of a MEK inhibitor alone may be as effective as adding a MEK inhibitor to an ALK inhibitor.SIGNIFICANCE STATEMENT This study contains in vivo evidence supporting the use of combination MEK inhibitors in ALK+ lung cancer research, both singularly and in combination with ALK inhibitors. Contrary to previously published reports, our results suggest that is possible to gain much of the benefit from combination treatment with a MEK inhibitor alone, at a tolerable dose.