Madison Bittner

Low-grade serous ovarian carcinoma (LGSOC) usually presents in advanced stages and is associated with a high mortality rate. Clinical trials targeting the MAPK and cell cycle pathways in LGSOC have shown promising results for its treatment, however there is a need to improve efficacy and define predictive biomarkers to guide patient selection for treatment using these agents. We therefore evaluated cell cycle protein expression by immunohistochemistry (IHC) in 186 LGSOC cases, and evaluated the efficacy of the MEK inhibitor, trametinib, in combination with the CDK4/6 inhibitor, palbociclib, in preclinical models of LGSOC. Abnormal p16 expression was observed in 20% of primary and 46% of recurrent tumors, and it was associated with poorer survival (log-rank p = 0.005). Notably, cell lines with increased sensitivity to trametinib were more likely to harbor mutations in KRAS or NF1 and displayed low pRb levels. Palbociclib showed limited efficacy in vitro; however, the combination of palbociclib and trametinib treatment produced synergistic antiproliferative effects in KRAS/NF1-wild-type cell lines, which displayed higher pRb levels. Acquired drug resistance was linked to increased cyclin D1/E1 expression. This study confirms abnormal p16 IHC as a negative prognostic marker in LGSOC and establishes key determinants of sensitivity to CDK4/6 inhibitor-based therapy.

Leung YY, et al. J Gynecol Oncol. 2025 Mar;36:e74. https://doi.org/10.3802/jgo.2025.36.e74

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.

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.

Supplementary Data from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition

Supplementary Data from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition

Supplementary Figure from NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition