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Updated: Aug 26, 2025
Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition
Marta Llaurado Fernandez1, E Marielle Hijmans2, Annemiek M C Gennissen2
1Department of Obstetrics and Gynaecology, University of British Columbia Vancouver, British Columbia, Canada.
Abstract:
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.
Insights
New research reveals a combination therapy targeting SHOC2 and MEK inhibitors (MEKi) effectively treats low-grade serous ovarian cancer (LGSOC). This pan-RAF inhibitor and MEKi combination overcomes MEKi resistance by downregulating HES1, offering a promising LGSOC treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Low-grade serous ovarian cancer (LGSOC) is a rare, aggressive subtype of epithelial ovarian cancer with poor outcomes due to chemoresistance.
- MAPK signaling pathway activation is a hallmark of LGSOC, making MEK inhibitors (MEKi) like trametinib a potential therapeutic option.
- Understanding and overcoming MEKi resistance mechanisms is crucial for improving LGSOC treatment strategies.
Purpose of the Study:
- To identify genes modulating the response to MEK inhibitors (MEKi) in LGSOC using genome-wide CRISPR-Cas9 screens.
- To discover novel drug combinations that can overcome MEKi resistance in LGSOC.
- To evaluate the efficacy of combining MEKi with pan-RAF inhibitors (pan-RAFis) in preclinical LGSOC models.
Main Methods:
- Utilized gain-of-function and loss-of-function CRISPR-Cas9 screens in LGSOC cell lines to identify resistance modulators.
- Investigated the role of NOTCH target HES1 in MEKi resistance.
- Performed synthetic lethality screens to identify drug combinations synergistic with MEKi, focusing on SHOC2.
- Tested the combination of pan-RAFis and MEKi in LGSOC cell lines, patient-derived ascites cultures, and xenograft mouse models.
Main Results:
- Overexpression of MAML2 and loss of MAP3K1 were identified as mechanisms conferring MEKi resistance, both leading to HES1 overexpression.
- Knockdown of HES1 reversed MEKi resistance, confirming its causal role.
- SHOC2 downregulation was found to be synthetic lethal with MEKi.
- The combination of pan-RAFis and MEKi demonstrated significant efficacy in parental, resistant LGSOC models, and patient-derived samples, downregulating HES1 in resistant cells.
Conclusions:
- The combination of MEK inhibitors (MEKi) with pan-RAF inhibitors (pan-RAFis) represents a promising therapeutic strategy for low-grade serous ovarian cancer (LGSOC).
- This combination effectively targets both sensitive and resistant LGSOC, potentially by downregulating HES1.
- Further clinical validation is warranted to translate these findings into improved patient treatment outcomes.
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