Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

Abstract

Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.

The pathognomonic FOXL2 C134W mutation alters DNA binding specificity

“…FOXL2 C134W induced targets are candidates for therapeutic intervention as they would be expected to show tumour specificity. SLC35F2, a putative direct target of FOXL2 C134W , encodes for a solute transporter previously shown to transport sepantronium bromide (YM155), a transcriptional suppressor of survivin expression having activity against a broad range of cancer types 47,48 (Fig. 5A).…”

Testing of the survivin suppressant YM155 in a large panel of drug-resistant neuroblastoma cell lines

“…However, DNA damage induction and Mcl-1 depletion were later suggested as additional or alternative anti-cancer mechanisms of YM155 [5,[11][12][13][14][15]. We recently confirmed that YM155 exerts its anti-neuroblastoma effects predominantly through survivin suppression [7]. YM155-induced survivin suppression proceeded DNA damage formation.…”

“…YM155-induced survivin suppression proceeded DNA damage formation. Moreover, YM155 mimicked the effects of RNAi-mediated survivin depletion, whereas Mcl-1 depletion did not affect neuroblastoma cell viability [7]. Furthermore, YM155-adapted UKF-NB-3 neuroblastoma cells had developed resistance to RNAi-mediated survivin depletion [7].…”

“…Survivin is a potential drug target in cancer entities including neuroblastoma [1][2][3][4][5][6][7], the most frequent solid extracranial paediatric cancer. About half of the patients are diagnosed with high-risk disease associated with overall survival rates below 50% despite myeloablative therapy and differentiation therapy using retinoids.…”

“…While many neuroblastomas respond initially well to therapy, acquired drug resistance represents a major clinical problem [8,9]. YM155 (sepantronium bromide) was introduced as a suppressor of survivin expression that displayed anti-cancer activity in pre-clinical models of different cancer entities including neuroblastoma [3][4][5]7,10]. However, DNA damage induction and Mcl-1 depletion were later suggested as additional or alternative anti-cancer mechanisms of YM155 [5,[11][12][13][14][15].…”