The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma

Abstract

Background Neuroblastoma is a deadly childhood cancer, and MYCN-amplified neuroblastoma (MNA-NB) patients have the worst prognoses and are therapy-resistant. While retinoic acid (RA) is beneficial for some neuroblastoma patients, the cause of RA resistance is unknown. Thus, there remains a need for new therapies to treat neuroblastoma. Here we explored the possibility of combining a MYCN-specific antigene oligonucleotide BGA002 and RA as therapeutic approach to restore sensitivity to RA in NB. Methods By molecular and cellular biology techniques, we assessed the combined effect of the two compounds in NB cell lines and in a xenograft mouse model MNA-NB. Results We found that MYCN-specific inhibition by BGA002 in combination with RA (BGA002-RA) act synergistically and overcame resistance in NB cell lines. BGA002-RA also reactivated neuron differentiation (or led to apoptosis) and inhibited invasiveness capacity in MNA-NB. Moreover, we found that neuroblastoma had the highest level of mRNA expression of mTOR pathway genes, and that BGA002 led to mTOR pathway inhibition followed by autophagy reactivation in MNA-NB cells, which was strengthened by BGA002-RA. BGA002-RA in vivo treatment also eliminated tumor vascularization in a MNA-NB mouse model and significantly increased survival. Conclusion Taken together, MYCN modulation mediates the therapeutic efficacy of RA and the development of RA resistance in MNA-NB. Furthermore, by targeting MYCN, a cancer-specific mTOR pathway inhibition occurs only in MNA-NB, thus avoiding the side effects of targeting mTOR in normal cells. These findings warrant clinical testing of BGA002-RA as a strategy for overcoming RA resistance in MNA-NB.

MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment

“…Different studies showed that MYCN over-expression is an obstacle to neuronal differentiation. High-risk and MYCN amplified neuroblastoma present a different transcriptional profile, where different pathways and genes related to differentiation are particularly altered [ 152 ]. Indeed, MYCN amplified neuroblastoma cell lines fail to differentiate in response to 13-cis-retinoic acid [ 8 ].…”

“…Indeed, MYCN amplified neuroblastoma cell lines fail to differentiate in response to 13-cis-retinoic acid [ 8 ]. The concomitant inhibition of MYCN and the administration of RA is able to reverse this block [ 152 ]. Moreover, the ectopic expression of MYCN in precursor cells blocks the differentiation in chromaffin cells.…”

“…Moreover, retinoic acid has been described as being capable of mTOR inhibition. While the N-Myc protein is stabilized by the mTOR complex, it also regulates the expression of different MTOR genes in a positive loop [ 152 , 184 ]. Indeed, MNA cell lines have a higher expression of mTOR genes, and they are more resistant to mTOR inhibitors.…”

“…Indeed, MNA cell lines have a higher expression of mTOR genes, and they are more resistant to mTOR inhibitors. Furthermore, it has been shown that mTOR is also negatively associated to the prognosis [ 152 ].…”

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

“…Moreover, while MYCN drives a tumor immunosuppressive environment, which impacts survival in several MYCN-positive tumors, the block of MYCN by the anti-MYCN BGA002 is able to reactivate and restore the effectiveness of the natural killer immune cells against NB [ 56 ]. It has been also found that BGA002 restores the retinoic acid (RA) response, leading to a differentiation or apoptosis in the MNA NB and also to a significant increase in survival in a mouse model of MNA-NB [ 57 ]. This study shows that it is possible to realize precision medicine by the identification of optimal combined drugs that can achieve a potent and selective block of cancer pathways only in tumor cells, preserving the impact of side effects on normal cells.…”