Fingolimod augments Pemetrexed killing of non-small cell lung cancer and overcomes resistance to ERBB inhibition.

Fingolimod augments Pemetrexed killing of non-small cell lung cancer and overcomes resistance to ERBB inhibition. Cancer Biol Ther. 2018 Nov 02;:1-11 Authors: Booth L, Roberts JL, Spiegel S, Poklepovic A, Dent P Abstract Overall, NSCLC has a poor 5-year survival and new therapeutic approaches are urgently needed. ERBB-addicted NSCLC that have become resistant to ERBB inhibitors are often refractory to additional therapeutic interventions. The sphingosine-1-phosphate receptor modulator fingolimod (FTY720), approved for the treatment of multiple sclerosis, synergized with the NSCLC therapeutic pemetrexed to kill NSCLC and ovarian cancer cells. This occurred in lung cancer cells expressing mutated K-RAS, mutated ERBB1, or in NSCLC cells resistant to afatinib (an ERBB1/2/4 inhibitor). This drug combination appeared to use overlapping and distinct mechanisms of killing in different cell lines. Activation of AMP-dependent kinase (AMPK) and reduced expression and inactivation of mTOR were associated with increased autophagosome and autolysosome formation. Downregulation of Beclin1 considerably reduced formation of autophagosomes and protected the cells from drug combination-induced killing without significantly altering autolysosome formation. Autophagy protein 5 (ATG5) knock down afforded greater protection against the combination of pemetrexed with fingolimod. Treatment of cells with the mTOR inhibitor everolimus markedly enhanced the let...
Source: Cancer Biology and Therapy - Category: Cancer & Oncology Authors: Tags: Cancer Biol Ther Source Type: research