MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer

Hew, Karina E.; Miller, Philip; El-Ashry, Dorraya; Sun, Jun; Besser, Alexandra H.; Ince, Tan A.; Gu, Mengnan; Wei, Zhi; Zhang, Gao; Brafford, Patricia; Gao, Wei; Lu, Yiling; Mills, Gordon B.; Slingerland, Joyce M.; Simpkins, Fiona

doi:10.1158/1078-0432.ccr-15-0534

Cited by 52 publications

(75 citation statements)

References 58 publications

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“…Despite a lack of mutations activating KRAS or BRAF in HGSOCs, we observed high levels of MEK1/2-ERK1/2 activity in a majority of clinical samples and cell lines. This observation is further supported by recently published studies reporting an association between high MAPK activity in HGSOC and poor survival [39,51]. Moreover, cisplatin treatment of HGSOC cells results in further MEK1/2 pathway activation that persists in cisplatin-resistant cells.…”

Section: Discussionsupporting

confidence: 77%

“…The function of the MEK1/2-ERK1/2 pathway has been mainly studied in low-grade ovarian tumors due to high frequency of activating KRAS and BRAF mutations [37,38]. Despite the absence of KRAS/BRAF mutations in HGSOC, MEK1/2 signaling hyperactivation was reported in HGSOC and is associated with poor prognosis [39]. The present paper aims to investigate the role of high MEK1/2 activity in the regulation of proliferation, viability, and stemness of HGSOC cells.…”

Section: Introductionmentioning

confidence: 99%

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The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

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Rationale: High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.Methods: MEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.Results: MEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133 + fraction and increased expression of stemness-associated genes.Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions. Conclusions: MEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumorgrowth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

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“…The abnormal activation of ERK1/2 pathway facilitates tumorigenesis, whereas, the stress-induced activation of JNK and p38MAPK controls the balance of cell autophagy and apoptosis [37, 38]. In this study, we observed that hnRNP-L upregulated p-ERK, p-p38 and p-JNK suggesting that hnRNP-L regulated cell fate in bladder cancer cells by promoting the MAPK (ERK/JNK/p38MAPK) signaling pathway.…”

Section: Discussionmentioning

confidence: 62%

HnRNP-L mediates bladder cancer progression by inhibiting apoptotic signaling and enhancing MAPK signaling pathways

Xing

et al. 2017

Oncotarget

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Heterogeneous nuclear ribonucleoprotein L (hnRNP-L) is a promoter of various kinds of cancers, but its actions in bladder cancer (BC) are unclear. In this study, we investigated the function and the underlying mechanism of hnRNP-L in bladder carcinogenesis. Our results demonstrated that enhanced hnRNP-L expression in BC tissues was associated with poor overall survival of BC patients. Depletion of hnRNP-L significantly suppressed cell proliferation in vitro and inhibited xenograft tumor growth in vivo. Furthermore, downregulation of hnRNP-L resulted in G1-phase cell cycle arrest and enhanced apoptosis accompanied by inhibition of EMT and cell migration. All these cellular changes were reversed by ectopic expression of hnRNP-L. Deletion of hnRNP-L resulted in decreased expression of Bcl-2, enhanced expression of caspases-3, -6 and -9 and inhibition of the MAPK signaling pathway. These findings demonstrate that hnRNP-L contributes to poor prognosis and tumor progression of BC by inhibiting the intrinsic apoptotic signaling and enhancing MAPK signaling pathways.

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“…RAS mutations are rare in BRCA1/2 mutated ovarian and breast cancers, but physiological pathway activation (6, 7) could mediate PARPi resistance, which could potentially be reversed by MEKi. In contrast, in other lineages such as pancreas and stomach, BRCA1/2 and KRAS mutations do co-occur (cBIOportal.org).…”

Section: Discussionmentioning

confidence: 99%

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

et al. 2017

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Mutant RAS has remained recalcitrant to targeted therapy efforts. Here we demonstrate that combined treatment with poly ADP ribose polymerase (PARP) inhibitors and MEK inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with: 1) induction of BIM-mediated apoptosis, 2) decrease in expression of components of the homologous recombination DNA repair pathway, 3) decrease in homologous recombination DNA damage repair capacity, 4) decrease in DNA damage checkpoint activity, 5) increase in PARP inhibitor-induced DNA damage, 6) decrease in vascularity which could increase PARP inhibitor efficacy by inducing hypoxia, and 7) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.

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MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer

Cited by 52 publications

References 58 publications

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

HnRNP-L mediates bladder cancer progression by inhibiting apoptotic signaling and enhancing MAPK signaling pathways

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

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