Inhibition of MEK alone and in combination with ALK inhibition suppresses tumor growth in a mouse model of ALK positive lung cancer

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 tha..... READ ARTICLE

Journal of Pharmacology and Experimental Therapeutics DOI:10.1124/jpet.120.266049

Authors: Nensi Shrestha, Abigail R Bland, Rebecca L Bower, Rhonda Rosengren, John Ashton

Pre-ClinicalKirk SmithApril 13, 2020ALK, MEK, Crizotinib, cancer, chemotherapy, receptor tyrosine kinases (RTKs)

Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin depen..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-019-55376-4

Authors: N. Shrestha, M. Nimick, P. Dass, R. J. Rosengren, J. C. Ashton

Pre-ClinicalKirk SmithDecember 11, 2019ALK, MEK, Crizotinib