Reference Detail

Ref Type

Journal Article

PMID

(36198031)

Authors

Llaurado Fernandez M, Hijmans EM, Gennissen AMC, Wong NKY, Li S, Wisman GBA, Hamilton A, Hoenisch J, Dawson A, Lee CH, Bittner M, Kim H, DiMattia GE, Lok CAR, Lieftink C, Beijersbergen RL, de Jong S, Carey MS, Bernards R, Berns K

Title

NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	21	12	2022 Dec 02	1862-1874	Mol Cancer Ther

URL

Abstract Text

Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian cancer with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC is characterized by activation of MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be a good treatment option for a subset of patients. Understanding MEKi-resistance mechanisms and subsequent identification of rational drug combinations to suppress resistance may greatly improve LGSOC treatment strategies. Both gain-of-function and loss-of-function CRISPR-Cas9 genome-wide libraries were used to screen LGSOC cell lines to identify genes that modulate the response to MEKi. Overexpression of MAML2 and loss of MAP3K1 were identified, both leading to overexpression of the NOTCH target HES1, which has a causal role in this process as its knockdown reversed MEKi resistance. Interestingly, increased HES1 expression was also observed in selected spontaneous trametinib-resistant clones, next to activating MAP2K1 (MEK1) mutations. Subsequent trametinib synthetic lethality screens identified SHOC2 downregulation as being synthetic lethal with MEKis. Targeting SHOC2 with pan-RAF inhibitors (pan-RAFis) in combination with MEKi was effective in parental LGSOC cell lines, in MEKi-resistant derivatives, in primary ascites cultures from patients with LGSOC, and in LGSOC (cell line-derived and patient-derived) xenograft mouse models. We found that the combination of pan-RAFi with MEKi downregulated HES1 levels in trametinib-resistant cells, providing an explanation for the synergy that was observed. Combining MEKis with pan-RAFis may provide a promising treatment strategy for patients with LGSOC, which warrants further clinical validation.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MAP2K1 F129L	ovarian serous carcinoma	resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, MAP2K1 F129L was identified in a low grade serous ovarian cancer cell line that developed resistance to treatment with Mekinist (trametinib) in culture (PMID: 36198031).	36198031
MAP2K1 F129L	ovarian serous carcinoma	resistant	Binimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, a low grade serous ovarian cancer cell line harboring MAP2K1 F129L was resistant to treatment with Mektovi (binimetinib) in culture (PMID: 36198031).	36198031
MAP2K1 F129L	ovarian serous carcinoma	resistant	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, a low grade serous ovarian cancer cell line harboring MAP2K1 F129L was resistant to treatment with Koselugo (selumetinib) in culture (PMID: 36198031).	36198031
MAP2K1 F129L	ovarian serous carcinoma	resistant	Refametinib	Preclinical - Cell culture	Actionable	In a preclinical study, a low grade serous ovarian cancer cell line harboring MAP2K1 F129L was resistant to treatment with Refametinib (BAY86-9766) in culture (PMID: 36198031).	36198031