Dihydroorotate dehydrogenase (DHODH) inhibition as a promising therapeutic strategy with synergistic targeting of ROR1 in small cell lung cancer

Small-cell lung cancer is an aggressive subtype of lung cancer with poor prognosis and comprises approximately 15% of all lung cancers. The frontline therapy for SCLC is platinum-etoposide chemotherapy. However, patients almost relapse shortly after the start of therapy, and second line therapies typically provide only a few months of benefit. Clearly, better therapeutics are necessary for the treatment of SCLC. Cancer cells often have dysregulated metabolic pathways. These changes are often necessary to enable the continued proliferation of cancer cells. Dihydroorotate dehydrogenase (DHODH), which catalyzes the conversion of dihydroorotate to orotate in the pyrimidine de novo synthesis pathway, has a particular role in the survival of multiple cancers including SCLC. Recent studies have shown that SCLC cells are thought to respond to therapy but recur due to a chemotherapy-resistant “stem cell” or “persister” population of tumor cells induced by therapy. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a receptor tyrosine kinase that is re-expressed in multiple cancers, including SCLC, where its expression is associated with shorter survival and rapid relapse. Therefore, targeting ROR1 may reduce stem-like tumor cells and improve therapeutic response in SCLC. We evaluated the effect of HOSU-53, a DHODH inhibitor, on SCLC tumor growth in vitro . We measured IC50s of 18 SCLC cell lines and most SCLC cells showed promising sensitivity to HOSU-53 treatment. However, some SCLC cells demonstrated resistance to DHODH inhibition. Therefore, we evaluated the synergy between HOSU-53 and KAN0441571C, a ROR1 inhibitor in vitro . SCLC cells were treated with the compounds as single agents as well as the combination. Synergy was observed between KAN0441571C and HOSU-53 in SCLC cells. To evaluate the effect of DHODH inhibition on SCLC tumor growth in vivo , we treated xenograft models with HOSU-53 alone or in combination with etoposide plus cisplatin. We observed a significant decrease in tumor volume when HOSU-53 was used alone and in combination, without significant animal weight loss. Additionally, to evaluate the effect of HOSU-53 and ROR1 inhibition on tumor burden in vivo , a treatment-resistant xenograft SCLC model was treated with HOSU-53 and KAN0441571C as single agents and the combination. We observed a significant reduction in tumor volume in the combination arm compared with the single-agent treatment arms, without significant loss of body weight. Together, these data demonstrated the promising efficacy of HOSU-53 as single agent as well as in combination with KAN0441571C in treatment-resistant SCLC models. These findings support the initiation of a phase l clinical trial to evaluate the preliminary efficacy and tolerability of HOSU-53 and support the strategy of targeting DHODH and ROR1 as a potential therapeutic approach for the treatment of SCLC.