Anaplastic lymphoma kinase harnesses the SLC4A7 bicarbonate transporter to intensify de novo nucleotide synthesis in neuroblastoma and lung cancer.

There is growing recognition of how metabolic dependencies influence sensitivity or resistance to neuroblastoma (NB) therapies. In this regard, the impact of Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase which is mutated in approximately 10% of primary NB cases, and a clinical target in NB on cellular metabolism is unclear. In this study, we combined phosphoproteomics and BioID-mediated proximity interaction screening in neuroblastoma cell lines, identifying the sodium bicarbonate transporter SLC4A7, a member of the Solute Carrier (SLC) family, and the multifunctional protein Carbamoyl Phosphate Synthetase 2-Aspartate Transcarbamylase-Dihydroorotase (CAD) downstream of ALK signaling in NB cells. SLC4A7 and CAD are both important molecular components in the metabolism of pyrimidine nucleotides. ALK activation leads to phosphorylation of both SLC4A7 and CAD, resulting in increased sodium bicarbonate transport and pyrimidine biosynthesis that is blocked by the addition of ALK tyrosine kinase inhibitors (TKIs). Combined targeting of both ALK signaling and nucleotide synthesis leads to a more effective inhibition of NB tumor growth in both cell and genetically modified mouse NB models. Finally, we show that SLC4A7 and CAD are also targets in ALK-driven non-small cell lung cancer (NSCLC), revealing a novel therapeutic strategy that leverages metabolomic dependencies to target ALK-driven malignancies such as NB and NSCLC.