Abstract 2019: Oxidative phosphorylation (OXPHOS) dependency predicts response to the Polo-like kinase 1 (PLK1) inhibitor onvansertib in a phase 1b/2 of relapsed/refractory acute myeloid leukemia (R/R AML)
Authors: Croucher Peter JP , Samuelsz Errin , Hassaine Latifa , Ross Brittany , Luebbermann Marion , Ridinger Maya , Erlander Mark 
Published: September 2020

Background: PLK1, a serine-threonine kinase and key regulator of the cell cycle, controls mitotic entry and progression. PLK1 is overexpressed in AML and its inhibition induces G2/M arrest, apoptosis and tumor growth inhibition in AML preclinical models. Onvansertib is the first PLK1-selective inhibitor orally bioavailable to enter the clinic, and has potent anti-tumor activity in AML models, including venetoclax-resistant models. A phase 1b/2 study (NCT03303339) is ongoing to assess the efficacy and safety of onvansertib in combination with decitabine or low-dose cytarabine (LDAC) in R/R AML. Correlative studies aim at identifying biomarkers associated with response to treatment.

Methods: R/R AML patients were dosed for 5 days with onvansertib (12 to 90 mg/m2) in combination with either decitabine (20 mg/m2 IV qd x 5d ) or LDAC (20 mg/m2 SC qd x 10d ) within a 21 to 28-day cycle. PLK1 inhibition is monitored by Western-Blot through changes in phosphorylation of its direct substrate: the translationally controlled tumor protein (TCTP). Target engagement (TE) was defined as ≥ 50% decrease in pTCTP/TCTP in blood samples collected at 3 hours versus pre-dose, in patients with at least 10% circulating blasts (CB). RNA-sequencing is performed on blood samples collected at pre-dose, 3h and 24h post-dose on day 1. To reduce dimensionality, gene counts were transformed into gene set enrichment (GSE) scores using GSVA, and corrected for %CB via ordination. GSE was evaluated for association with clinical response or TE via permutation T-tests and machine learning.

Results: Target engagement (TE) in CB was observed in only 8 (33%) of the 24 evaluable patients. TE was associated with higher response to treatment as measured by decrease in BM %blasts and objective responses (CR/CRi). TE was not dependent on onvansertib dose level, pharmacokinetics, or combination treatment.

At pre-dose, TE patients had a notable upregulation of OXPHOS, DNA repair, and proliferative pathways. Responders (CR/CRi, n=5) versus non-responders (n=25) showed a similar upregulation of OXPHOS plus stress and immune related pathways, and downregulation of glycolysis. Comparison of baseline versus treatment (3h and 24h), TE and responder samples exhibited similar changes, with a strong decrease in metabolic processes, including: OXPHOS, mTORC1 signaling, and glycolysis.

Conclusion: Our analyses identified OXPHOS as an up-regulated pathway at baseline associated with response to onvansertib (TE and CR/CRi) that is subsequently down-regulated post-therapy. OXPHOS driven metabolism is characteristic of leukemic stem cells and chemo-resistant AML, therefore patients resistant to conventional chemo-treatments may benefit from the addition of onvansertib.

Citation Format: Peter JP Croucher, Errin Samuelsz, Latifa Hassaine, Brittany Ross, Marion Luebbermann, Maya Ridinger, Mark Erlander. Oxidative phosphorylation (OXPHOS) dependency predicts response to the Polo-like kinase 1 (PLK1) inhibitor onvansertib in a phase 1b/2 of relapsed/refractory acute myeloid leukemia (R/R AML) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2019.