Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer

Swearingen, Amanda E.D. Van; Sambade, Maria J.; Siegel, Marni B.; Sud, Shivani; McNeill, Robert S.; Bevill, Samantha M.; Chen, Xin; Bash, Ryan; Mounsey, Louisa; Golitz, Brian T.; Santos, Charlene; Deal, Allison M.; Parker, Joel S.; Rashid, Naim U.; Miller, C. Ryan; Johnson, Gary L.; Anders, Carey K.

doi:10.1093/neuonc/nox052

Cited by 33 publications

(26 citation statements)

References 50 publications

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“…Several PDGFR and Stat3 inhibitors have been developed and are used primarily for the treatment of TNBC patients whose tumors have enriched CSCs and show poor prognosis. Previous studies have suggested that combination of the PDGFR inhibitor pazopanib with other kinase inhibitors produces improved efficacy in the treatment of TNBC (Gril et al 2013;Van Swearingen et al 2017). Similarly, targeting STAT3 by its inhibitors also resulted in a promising response against TNBC .…”

Section: Discussionmentioning

confidence: 99%

CD44 splice isoform switching determines breast cancer stem cell state

et al. 2019

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Although changes in alternative splicing have been observed in cancer, their functional contributions still remain largely unclear. Here we report that splice isoforms of the cancer stem cell (CSC) marker CD44 exhibit strikingly opposite functions in breast cancer. Bioinformatic annotation in patient breast cancer in The Cancer Genome Atlas (TCGA) database reveals that the CD44 standard splice isoform (CD44s) positively associates with the CSC gene signatures, whereas the CD44 variant splice isoforms (CD44v) exhibit an inverse association. We show that CD44s is the predominant isoform expressed in breast CSCs. Elimination of the CD44s isoform impairs CSC traits. Conversely, manipulating the splicing regulator ESRP1 to shift alternative splicing from CD44v to CD44s leads to an induction of CSC properties. We further demonstrate that CD44s activates the PDGFRβ/Stat3 cascade to promote CSC traits. These results reveal CD44 isoform specificity in CSC and non-CSC states and suggest that alternative splicing provides functional gene versatility that is essential for distinct cancer cell states and thus cancer phenotypes.

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Section: Discussionmentioning

confidence: 99%

CD44 splice isoform switching determines breast cancer stem cell state

et al. 2019

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“… 116 117 Another recent data reported a therapeutic synergy when combining the MEK inhibitor selumetinib with either buparlisib or the platelet-derived growth factor receptor inhibitor pazopanib, which was even effective for brain metastases of TNBC. 118 Among numerous combination trials of MEK inhibitors currently ongoing, a phase Ib trial combining the MEK inhibitor trametinib with gemcitabine in advanced solid tumours showed a case of complete response in the patient with metastatic TNBC. 119 On the other hand, phase I trials evaluating combination treatment of MEK inhibitors either with mTOR or PI3K inhibitors (NCT01476137, NCT0095573) revealed unacceptable fatal toxicities, prohibiting subsequent phase II studies.…”

Section: Upcoming Treatment Options Beyond Conventional Chemotherapymentioning

confidence: 99%

How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies

2018

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Triple-negative breast cancer (TNBC) is a long-lasting orphan disease in terms of little therapeutic progress during the past several decades and still the standard of care remains chemotherapy. Experimental discovery of molecular signatures including the ‘BRCAness’ highlighted the innate heterogeneity of TNBC, generating the diversity of TNBC phenotypes. As it contributes to enhancing genomic instability, it has widened the therapeutic spectrum of TNBC. In particular, unusual sensitivity to DNA damaging agents was denoted in patients with BRCA deficiency, suggesting therapeutic benefit from platinum and poly(ADP-ribose) polymerase inhibitors. However, regardless of enriched chemosensitivity and immunogenicity, majority of patients with TNBC still suffer from dismal clinical outcomes including early relapse and metastatic spread. Therefore, efforts into more precise and personalised treatment are critical at this point. Accordingly, the advance of multiomics has revealed novel actionable targets including PI3K-Akt-mTOR and epidermal growth factor receptor signalling pathways, which might actively participate in modulating the chemosensitivity and immune system. Also, TNBC has long been considered a potential protagonist of immunotherapy in breast cancer, supported by abundant tumour-infiltrating lymphocytes and heterogeneous tumour microenvironment. Despite that, earlier studies showed somewhat unsatisfactory results of monotherapy with immune-checkpoint inhibitors, consistently durable responses in responders were noteworthy. Based on these results, further combinatorial trials either with other chemotherapy or targeted agents are underway. Incorporating immune-molecular targets into combination as well as refining the standard chemotherapy might be the key to unlock the future of TNBC. In this review, we share the current and upcoming treatment options of TNBC in the framework of scientific and clinical data, especially focusing on early stage of TNBC.

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“…To strengthen our findings with PD98059, we also tested selumetinib (AZD6244), a potent, highly selective MEK1/12 inhibitor, in tumorsphere assays. Selumetinib has shown promise as a potential therapy for treatment of triple-negative breast cancer brain metastases (41) and glioblastoma (39) in preclinical animal models. Importantly, selumetinib crosses the blood brain barrier and is currently in clinical trials for treatment of pediatric refractory low-grade glioma (42).…”

Section: Mek1/2 Inhibition Decreases Cd271 Levels As Well As Prolifermentioning

confidence: 99%

“…As selumetinib significantly decreases CD271 levels, cell proliferation, survival and migration in vitro and is also known to be brain penetrant (39,41), we tested the effect of this MEK1/2 inhibitor in our mouse xenograft model. Intracerebellar injections of 2.5 Â 10 5 UI226 tumorspheres cells were performed in NOD/ SCID mice.…”

Section: Mek1/2 Inhibition Significantly Increases Survival and Reducmentioning

confidence: 99%

CD271+ Cells Are Diagnostic and Prognostic and Exhibit Elevated MAPK Activity in SHH Medulloblastoma

et al. 2018

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The extensive heterogeneity both between and within the medulloblastoma subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH medulloblastoma subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH medulloblastoma using IHC analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271 and CD271 cells revealed molecularly distinct, coexisting cellular subsets, both and MAPK/ERK signaling was upregulated in the CD271 population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels, whereas, treatment with vismodegib, a well-known smoothened (SMO) inhibitor currently in clinical trials for the treatment of recurrent SHH medulloblastoma, had no significant effect in our models. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH medulloblastoma tumors and reveals a novel role for MEK inhibitors in targeting CD271 SHH medulloblastoma cells. This study identifies CD271 as a specific and novel biomarker of SHH-type medulloblastoma and that targeting CD271 cells through MEK inhibition represents a novel therapeutic strategy for the treatment of SHH medulloblastoma. .

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Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer

Cited by 33 publications

References 50 publications

CD44 splice isoform switching determines breast cancer stem cell state

CD44 splice isoform switching determines breast cancer stem cell state

How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies

CD271+ Cells Are Diagnostic and Prognostic and Exhibit Elevated MAPK Activity in SHH Medulloblastoma

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