Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma

Abstract

Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ()-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with knockdown PCPG allograft. In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with mutations..

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…As noted above another way to become resistant to chemotherapy is via the NAD + /PARP‐pathway. In the study of Pang et al the combination of temozolomide with a PARP inhibitor led to increased mouse survival in a metastatic PGL/PCC allograft model (52 days compared with 42 days) . Notably, one of the postulated pathways through which metformin exerts an anti‐tumor effect is also through inhibition of complex I, implying that metformin could also act as a potential chemosensitizer in patients with SDHx ‐related metastatic PGL/PCC.…”

“…Tannahill et al and Imperiale et al also showed an increased import and metabolism of glutamine in SDHxrelated tumors. 105,Oxidative phosphorylation Disruption of complex II leads to changes in the TCA cycle, but also to changes in oxidative phosphorylation in the form of upregulation of complex I. Pang et al showed that in tumor tissue and in an SDHBknockdown mouse cell line, complex I components and activity are upregulated 107. Consequently, the quantity of NAD + in tumor tissue was 2.7-fold higher in cluster I than in cluster II tumors.…”

Targeting NRF2-Governed Glutathione Synthesis for SDHB-Mutated Pheochromocytoma and Paraganglioma

“…For example, Hadoux et al discovered that temozolomide was more effective against metastatic SDHB PCPG due to low O 6 -alkylguanine DNA alkyltransferase (MGMT) methylation status [18]. In addition, Sulkowski, as well as our group, discovered that SDHB PCPGs exhibit higher sensitivity to a combination regimen involving a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor and genotoxic agent, as this type of malignancy exhibits a deficiency of homologous recombination DNA repair and nicotinamide adenine dinucleotide (NAD) metabolism [19,20]. Overall, these findings imply that therapeutic regimens can be optimized by targeting the unique molecular signature(s) of cluster I PCPGs.…”

Metastatic Phaeochromocytoma: Spinning Towards More Promising Treatment Options

“…PARP inhibitors, which have been demonstrated to potentiate DNA damaging effects of chemotherapeutic agents [110,111], could be a promising target for metastatic PCCs/PGLs with cluster-1 mutations such as SDHB. In a very recent study in an allograft mouse model of SDHB-knockdown PCC/PGLs, therapy with the PARP inhibitor olaparib sensitised PCC/PGL cells to temozolomide, suppressed metastatic allograft lesions and improved overall survival [112]. The NAD + /PARP pathway might be a crucial target in SDHB-mutated PCC/PGL.…”