Classic and targeted anti-leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications.

Fangli Chen,George A Calin,Heiko Konig,Marilena Gilca,Cristina Niculite,Bin Guo,Adriana Rogozea,Susan Rice,Daniela Petrusca,H Scott Boswell,Xue Wu,Shawn Griffin

doi:10.1111/jcmm.15339

Abstract

Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O2, ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O2 environments.

Highlights

Decreased O2 tension in the neoplastic microenvironment is a well-established determinant of therapy failure and disease relapse in cancer; the experimental evidence remains heavily biased towards solid tumours.[42,43]
In the case of acute myeloid leukaemia (AML), hypoxic niches are naturally present in the bone marrow and are generally thought to act as therapeutic shelters for leukaemic cells.[17]
We explored the molecular responses of FMS-like tyrosine kinase 3/internal tandem duplication–mutated (FLT3/ITD+) AML cells to cytarabine and the highly selective FLT3 inhibitor quizartinib under O2-controlled conditions in vitro

Summary

| INTRODUCTION

The dramatic progress in deciphering the molecular architecture of acute myeloid leukaemia (AML) has led to the development of a new generation of targeted therapeutic agents, such as the multitargeted kinase inhibitor midostaurin, the isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib, and the B-cell lymphoma (Bcl)-2 and Hedgehog pathway inhibitors venetoclax and glasdegib, respectively, which recently received FDA approval.[1,2,3,4,5] Despite these undeniable advances, only a limited subset of patients is expected to benefit from such agents, due to the vast molecular heterogeneity and complex clonal architecture of AML.[6,7] Based on extensive pre-clinical and clinical literature, single anti-AML drugs, whether targeted or not, fail to eliminate minimal residual disease (MRD), with relapse generally occurring within three years from diagnosis.[8,9,10,11,12] Overall, the disconnect between the wealth of basic knowledge and dismal clinical outcome remains a defining feature of AML, with the vast majority of patients still relying on cytarabine, a nonspecific nucleoside analog introduced more than four decades ago, as the backbone of most chemotherapeutic regimens.[13]. Several lines of evidence suggest that O2-deprived (hypoxic) niches within the bone marrow (BM) play a central role in AML drug resistance and disease relapse.[16,17] In tissue culture experiments, O2 concentrations between 1% and 5% are thought to better mimic oxygenation levels experienced by leukaemic cells in their natural environment.[18,19,20,21] Despite accumulating evidence for diverse artefact-producing effects of excessive oxygenation,[22,23] AML in vitro studies are still routinely performed under atmospheric oxygenation (21% O2, ambient air), with potentially significant translational consequences. We used a conceptually similar strategy to extract information about potential synergistic therapeutic partnerships in the context of solid tumours.[25,26] For practical reasons, the initial screens were performed in an established AML cell line (Molm[14], M14), with subsequent validation experiments extended to a diverse panel, including primary leukaemic cells. The results presented have significant translational implications, as they provide support for the value of adding higher-potency statins (eg rosuvastatin) to classical and emerging AML therapies

| METHODS

Findings

| DISCUSSION