Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

Choi, Peter S.; Li, Yulin; Felsher, Dean W.

doi:10.1073/pnas.1406123111

Cited by 14 publications

(10 citation statements)

References 48 publications

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“…This may be a limiting factor for the usefulness of these compounds as MYC activation is a later event in myeloid leukemias that are not triggered by a translocation or amplification directly affecting MYC . This is an important consideration because when additional oncogenes together with MYC drove AML development, removal of MYC expression failed to prevent tumor recurrence …”

Section: Discussionmentioning

confidence: 99%

BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML

Zhang

Zhao

Heaster

et al. 2018

J of Cellular Biochemistry

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Inhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G0/G1 arrest, and with time, cause cell death. Meta‐analysis of PRO‐seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addition, gene expression analysis showed that transcription of BCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 inhibitor, venetoclax, in combination with the BETi was a potent combination in t(8;21) containing cells. Thus, BET inhibitors that affect MYC and BCL2 expression should be considered for combination therapy with venetoclax.

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Section: Discussionmentioning

confidence: 99%

BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML

Zhang

Zhao

Heaster

et al. 2018

J of Cellular Biochemistry

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“…It has been speculated that failures of therapies targeting single oncogenes are due to resistance mechanisms arising from acquisition of other activating mutations affecting additional signaling pathways [ 53 ]. Choi et al have recently reported evidence in support of this concept [ 54 ]. Their results suggest that DFMO combinations targeting other genetic features of NB [ 55 – 57 ] may be beneficial to patients not responding adequately to DFMO+/- etoposide.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma

et al. 2015

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BackgroundNeuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.Methods and FindingsTwenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056).ConclusionsDFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.Trial RegistrationClinicaltrials.gov NCT#01059071

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“…compared to treatment with the single drug, but adding a third drug did not lead to a significant benefit. The benefits of combining targeted therapies over monotherapies have been demonstrated both in preclinical models of lymphoma and colorectal cancer (Choi et al 2014, Misale et al 2015 and in clinical trials of BRAF-mutated melanoma (Larkin et al 2014, Long et al 2014, Robert et al 2015. Combination of two anti-HER2 monoclonal antibodies, pertuzumab and trastuzumab, together with the chemotherapy drug docetaxel was more effective than trastuzumab and docetaxel alone for treatment of HER2-positive breast cancer (Baselga et al 2012, Swain et al 2015.…”

Section: Cross-resistancementioning

confidence: 99%

Resisting Resistance

Božić

Nowak

2017

Annu. Rev. Cancer Biol.

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Targeted therapies, immunotherapies, and improved chemotherapies are being developed to reduce the suffering and mortality that come from human cancer. Although these approaches, and in particular combinations of them, are expected to succeed eventually to a large degree, they all suffer one obstacle: Populations of replicating cells move away-typically in a high-dimensional space-from any opposing selection pressure they encounter. They evolve resistance. It is possible, however, to develop a precise mathematical understanding of the problem and to design treatment strategies that prevent resistance if possible or manage resistance otherwise. In this article, we present the fundamental equations that characterize the evolution of resistance. We provide formulas for the probability that resistant cells exist at the start of therapy, for the average number and sizes of resistant clones, and for the probability of successful combination treatment. We also demonstrate that developing new therapies that only maximize the killing rate of cancer cells may not be optimal, and that instead the parameters determining the fraction of resistant cells and their growth rate have a larger effect on the long-term control of cancer. These mathematical tools inform the search process for optimal therapies that aim to cure cancer.

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Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

Cited by 14 publications

References 48 publications

BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML

BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma

Resisting Resistance

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