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

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 lethality of pemetrexed plus fingolimod combination. Our data suggest that the combination of fingolimod with the established NSCLC/ovarian cancer drug pemetrexed should be explored as a new therapy.

Keywords:

• autophagy
• HDAC
• sphingolipid

Acknowledgments

Support for the present study was funded from philanthropic funding from Massey Cancer Center, the Universal Inc. Chair in Signal Transduction Research and PHS R01-CA192613 (PD) and R01GM043880 (SS). Thanks to Dr. H.F. Young and the Betts family fund for support in the purchase of the Hermes Wiscan instrument.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Supplementary material

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