Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers

Hata, Aaron N.; Rowley, Steve; Archibald, Hannah L.; Gomez‐Caraballo, María; Siddiqui, Faria M.; Ji, Fei; Jung, Joonil; Light, Madelyn; Lee, Joon Sang; Debussche, Laurent; Sidhu, Sukhvinder; Sadreyev, Ruslan I.; Watters, James; Engelman, Jeffrey A.

doi:10.1038/onc.2017.258

Cited by 31 publications

(34 citation statements)

References 56 publications

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“…This indicates that MV4-11 and OCI-AML-2 contain pre-existing TP53 -mutant subpopulation that are selected by nutlin-3 treatment, while nutlin-3 treatment resulted in de novo TP53 mutations in OCI-AML-3 and SIG-M5. These results are consistent with those obtained from other cancer entities [35,36,39,41].…”

Section: Resultssupporting

confidence: 92%

“…MDM2 inhibitors are currently being investigated in phase II and III clinical trials for AML (NCT02670044, NCT02545283). In various cell types, resistance formation to MDM2 inhibitors has previously been shown to be associated with the selection of pre-existing TP53 -mutant cancer cell populations or the induction of de novo TP53 mutations [3,35,36,39,41]. A clinical trial in liposarcoma patients confirmed that MDM2 inhibitor therapy is also associated with the emergence of TP53 mutations in the clinic [40].…”

Section: Discussionmentioning

confidence: 99%

“…The origin of MDM2 inhibitor-induced TP53 mutations in TP53 wild-type cell lines is not entirely clear. In dependence of the cell line model, MDM2 inhibitors may induce a range of different de novo TP53 mutations in a given model or select small, pre-existing cell fractions that harbour TP53 mutations [35,36,39,41].…”

Section: Introductionmentioning

confidence: 99%

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TP53mutations and drug sensitivity in acute myeloid leukaemia cells with acquired MDM2 inhibitor resistance

Michaelis

Schneider

Rothweiler

et al. 2018

Preprint

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Background:MDM2 inhibitors are under investigation for the treatment of acute myeloid leukaemia (AML) patients in phase III clinical trials. To study resistance formation to MDM2 inhibitors in AML cells, we here established 45 sub-lines of the AML TP53 wild-type cell lines MV4-11 (15 sub-lines), OCI-AML-2 (10 sub-lines), OCI-AML-3 (12 sub-lines), and SIG-M5 (8 sub-lines) with resistance to the MDM2 inhibitor nutlin-3.Methods: Nutlin-3-resistant sub-lines were established by continuous exposure to stepwise increasing drug concentrations. The TP53 status was determined by next generation sequencing, cell viability was measured by MTT assay, and p53 was depleted using lentiviral vectors encoding shRNA.Results:All MV4-11 sub-lines harboured the same R248W mutation and all OCI-AML-2 sub-lines the same Y220C mutation, indicating the selection of pre-existing TP53-mutant subpopulations. In concordance, rare alleles harbouring the respective mutations could be detected in the parental MV4-11 and OCI-AML-2 cell lines. The OCI-AML-3 and SIG-M5 sub-lines were characterised by varying TP53 mutations or wild type TP53, indicating the induction of de novo TP53 mutations. Doxorubicin, etoposide, gemcitabine, cytarabine, and fludarabine resistance profiles revealed a noticeable heterogeneity among the sub-lines even of the same parental cell lines. Loss-of-p53 function was not generally associated with decreased sensitivity to cytotoxic drugs.Conclusion:We introduce a substantial set of models of acquired MDM2 inhibitor resistance in AML. MDM2 inhibitors select, in dependence on the nature of a given AML cell population, pre-existing TP53-mutant subpopulations or induce de novo TP53 mutations. Although loss-of-p53 function has been associated with chemoresistance in AML, nutlin-3-adapted sub-lines displayed in the majority of experiments similar or increased drug sensitivity compared to the respective parental cells. Hence, chemotherapy may remain an option for AML patients after MDM2 inhibitor therapy failure. Even sub-lines of the same parental cancer cell line displayed considerable heterogeneity in their response to other anti-cancer drugs, indicating the need for the detailed understanding and monitoring of the evolutionary processes in cancer cell populations in response to therapy as part of future individualised treatment protocols.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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TP53mutations and drug sensitivity in acute myeloid leukaemia cells with acquired MDM2 inhibitor resistance

Michaelis

Schneider

Rothweiler

et al. 2018

Preprint

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“…Resistance can occur by selection of pre-existing drug-resistant subpopulations or by adaptation of originally drug-sensitive cells to anti-cancer therapies. Both mechanisms have been shown to be represented in drug-adapted cancer cell lines [52,[66][67][68][69][70][90][91][92][93][94][95][96][97][98][99][100][101] .…”

Section: Multiple Resistance Models Are Needed To Reflect the Heterogmentioning

confidence: 99%

Drug-adapted cancer cell lines as preclinical models of acquired resistance

Michaelis¹,

Wass²,

Činátl³

2019

CDR

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Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

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“…Acquired resistance mechanisms are still not understood, especially in glioblastoma. Potential mechanisms leading to acquired MDM2 inhibitor resistance are p53 mutations (21)(22)(23)(24) as well as enhanced B-cell lymphoma-extra-large (Bcl-xl) or MDM4 protein expression, offering the opportunity to be targeted by the addition of specific inhibitors (25).…”

Section: Introductionmentioning

confidence: 99%

Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib

Berberich

Keßler

Thomé

et al. 2019

Clinical Cancer Research

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Purpose: Resistance is an obstacle of glioma therapy. Despite targeted interventions, tumors harbor primary resistance or become resistant over short course of treatment. This study examined the mouse double minute 2 (MDM2) inhibitor RG7388 together with radiotherapy and analyzed strategies to overcome acquired MDM2 inhibitor resistance in glioblastoma.Experimental Design: Effects of RG7388 and radiotherapy were analyzed in p53 wild-type glioblastoma cell lines and glioma-initiating cells. RG7388 resistant cells were generated by increasing RG7388 doses over 3 months. Regulated pathways were investigated by microarray, qRT-PCR, and immunoblot analysis and specifically inhibited to evaluate rational salvage therapies at RG7388 resistance. Effects of RG7388 and trametinib treatment were challenged in an orthotopical mouse model with RG7388 resistant U87MG glioblastoma cells.Results: MDM2 inhibition required functional p53 and showed synergistic activity with radiotherapy in first-line treatment. Long-term exposure to RG7388 induced resistance by activation of the extracellular signal-regulated kinases 1/2 (ERK1/2)-insulin growth factor binding protein 1 (IGFBP1) signaling cascade, which was specifically overcome by ERK1/2 pathway inhibition with trametinib and knockdown of IGFBP1. Combining trametinib with continued RG7388 treatment enhanced antitumor effects at RG7388 resistance in vitro and in vivo.Conclusions: These data provide a rationale for combining RG7388 and radiotherapy as first-line therapy with a specific relevance for tumors insensitive to alkylating standard chemotherapy and for the addition of trametinib to continued RG7388 treatment as salvage therapy after acquired resistance against RG7388 for clinical practice.

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Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers

Cited by 31 publications

References 56 publications

TP53mutations and drug sensitivity in acute myeloid leukaemia cells with acquired MDM2 inhibitor resistance

TP53mutations and drug sensitivity in acute myeloid leukaemia cells with acquired MDM2 inhibitor resistance

Drug-adapted cancer cell lines as preclinical models of acquired resistance

Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib

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