Small Molecule Shows Marked Activity Against Ibrutinib-Resistant MCL

Michael Wang, MD

Preclinical data suggest that the small molecule IACS-10759, which targets the oxidative phosphorylation (OXPHOS) and glutaminolysis pathways, may play a critical role in overcoming resistance to ibrutinib (Imbruvica) in mantle cell lymphoma (MCL).^1,2

In the translational study published in Science Translational Medicine, results showed that metabolic reprogramming through these pathways enables tumor growth and survival. By inhibiting OXPHOS, researchers demonstrated marked growth inhibition in vivo and in vitro, in ibrutinib-resistant, patient-derived xenograft (PDX) mouse models. Little effect was observed in ibrutinib-sensitive MCL cell lines.

The inhibitor of electron transport chain (ETC) complex I significantly reduced ETC complex I activity in an in vitro enzymatic assay in ibrutinib-resistant MCL cell lines after treatment (P = .0041). The oxygen consumption rate was also reduced in the ibrutinib-resistant MCL cell lines compared with ibrutinib-sensitive MCL cell lines.

“We showed that metabolic reprogramming toward OXPHOS and glutaminolysis is associated with therapeutic resistance to ibrutinib in mantle cell lymphoma, an incurable B-cell lymphoma with poor clinical outcomes. Inhibition of OXPHOS with IACS-10759 results in marked growth inhibition in vivo and in vitro in ibrutinib-resistant, patient-derived cancer models,” lead study author Michael Wang, MD, professor of Lymphoma and Melanoma at The University of Texas MD Anderson Cancer Center, said in a press release.

To understand the underlying resistance mechanisms to ibrutinib, researchers collected 37 clinical samples from patients with MCL treated with ibrutinib. Whole-exome sequencing was performed on 14 samples for which there was sufficient tumor DNA, revealing an even number of ibrutinib-resistant and -sensitive patients.

Whole-transcriptome RNA sequencing was then performed on 15 ibrutinib-sensitive and 6 ibrutinib-resistant MCL samples. Ibrutinib-resistant samples enriched for the expression of genes regulated by OXPHOS, which is often promulgated by glutaminolysis. Further, ibrutinib-resistant MCL cell lines revealed higher basal, adenosine 5’-triphosphate—coupled, and reserve oxygen consumption rates.

To confirm the activity observed in vitro, investigators administered 10 mg/kg of oral IACS-010759 5 days per week to an ibrutinib-resistant MCL PDX mouse model derived from a patient with ibrutinib-resistant MCL. The treatment eradicated all tumor growth compared with vehicle control as assessed by tumor volume (n = 5; P <.0001). The agent was administered without any evidence of toxicity. Furthermore, there were no significant differences in body weight between the MCL PDX mice (P = .3304).

“To investigate the therapeutic effects of IACS-10759, we developed an ibrutinib-resistant B-cell lymphoma mouse model using tumor cells isolated from cerebrospinal fluid from a patient who did not respond to multiple therapies including ibrutinib,” said Wang.

A second ibrutinib-resistant mouse model was created to verify the initial suppression in tumor growth in vitro. IACS-010759 showed a significant reduction in tumor volume compared with the control (n = 5; P < .001). Further, no significant weight loss was reported in the IACS-010759 treatment arm (P = .0025). Moreover, IACS-010759 prolonged survival of a median 11 days in ibrutinib-resistant MCL PDX mice versus the control (n = 5; P = .0027).

The inhibitor also showed activity in more aggressive and refractory double hit B-cell lymphoma with central nervous system involvement gathered from patients’ cerebrospinal fluid. Notably, IACS-010759 reduced tumor growth (P <.0001), extending median survival by more than 20 days.

Ibrutinib was approved by the FDA in 2013 for the treatment of patients with relapsed/refractory MCL. However, 1-year survival rates after relapse on ibrutinib remain low at 22%.

“The study warrants the exploitation of active cancer metabolic pathways, especially OXPHOS and glutaminolysis, to improve clinical outcomes for mantle cell lymphoma and other lymphomas,” added co-senior author Linghua Wang, PhD, assistant professor of Genomic Medicine at The University of Texas MD Anderson Cancer Center.

Accordingly, a phase I study targeting the OXPHOS and glutaminolysis pathways in lymphoma is currently underway (NCT03291938). The agent is also under investigation in phase I clinical trials in acute myeloid leukemia (NCT02882321) in addition to solid tumors and lymphoma (NCT03291938).

References

1. Zhang L, Yao Y, Zhang S, et al. Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma. Sci Transl Med. 2019;11(1167).
2. Study shows MD Anderson-developed drug effective in overcoming ibrutinib resistance in mantle cell lymphoma. The University of Texas MD Anderson Cancer Center. Published May 8, 2019. https://bit.ly/2VYOCJL. Accessed May 10, 2019.