Ovarian cancer is a heterogeneous disease, with subtypes classified by site of origin, pathology, histologic grade, cell surface biomarkers, and molecular drivers. Approximately 20,890 new cases of ovarian cancer are diagnosed per year in the United States with an estimated 12,730 deaths per year [1]. Epithelial ovarian cancers include high grade serous cancer (HGSC), low-grade serous cancer (LGSC) [2], and other uncommon histologic subtypes including mucinous, clear cell, and endometrioid. HGSC is the most common subtype (∼75 % of epithelial ovarian cancers). HGSCs are typically responsive initially to platinum-based chemotherapy, but most patients eventually experience a relapse of their cancer with progressive treatment resistance driven by multiple mechanisms of resistance [3]. LGSC occurs less commonly than HGSC, is typically less sensitive to platinum-based chemotherapy, and often harbors molecular alterations within the RAS-MEK-ERK pathway [4,5].

The clinical aspects of LGSC have been extensively reviewed in other publications [2,4,6]. In 2020, the World Health Organization (WHO) defined LGSC as an invasive serous neoplasm with low-grade malignant features [7]. This histologic subtype predominantly occurs in younger women and may arise in association with pre-malignant serous borderline tumors (SBT). While SBT are primarily managed surgically, patients with advanced stage LGSC are treated upfront with both surgery and chemotherapy; despite this, most patients with LGSC experience persistent or recurrent disease. While LGSC patients have comparatively better prognosis at the time of diagnosis, the disease is nearly uniformly fatal once it spreads to the peritoneal cavity. LGSC is characterized by frequent mutations in KRAS, NRAS, and BRAF, and is relatively insensitive to chemotherapy but responsive to hormonal therapies and MEK inhibition, which represent standards of care in this histology [4,5].

The RAS-MEK-ERK pathway (Fig. 1) is frequently activated or altered in multiple histologic subtypes of ovarian cancer through gene mutations and/or amplifications, making this pathway an attractive target in ovarian cancer. RAS proteins (KRAS, HRAS, NRAS) exist in two interchangeable states, an active GTP-bound form and an inactive GDP-bound form [[8], [9], [10]]. Upstream signaling from growth factor receptors (and associated mediators such as GRB2, SOS1, and SHP2) leads to activation of RAS, which signals downstream to RAF, MEK, and ERK, as well as other parallel pathways including the PI3K pathway. Activated ERK translocates to the nucleus and modulates multiple other proteins, leading to diverse cellular changes in cellular proliferation, survival, cell cycle progression, apoptosis, and differentiation.

Genetic alterations in the RAS-MEK-ERK pathway are common in non-HGS ovarian tumors including LGSC, SBT, and mucinous and endometrioid ovarian cancers [5,[11], [12], [13], [14], [15], [16]] (Fig. 2). A majority of SBTs and LGSCs contain mutually exclusive mutations in either KRAS, BRAF, or NRAS [5,13,14,[17], [18], [19], [20]]. For example, the frequency of KRAS mutations has been reported to be 19 % to 54 % in LGSCs and 17 % to 40 % in SBTs [17]. Most of these KRAS mutations are non-G12C, such as G12D or G12V, or more rare alterations such as G12X, G12A, G12S, and G12R [16,21]. In one study, the frequency of KRAS G12D mutation in LGSC was 19.5 % and KRAS G12V was 20.3 %, whereas KRAS G12C was only 0.8 % [16]. In another series of LGSC arising from SBT, 8/23 (34.8 %) patients had KRAS G12D, 5/23 (21.7 %) had KRAS G12V, 2/23 (8.7 %) had KRAS G12A, and 0/23 (0 %) had KRAS G12C in the SBT, LGSC, or both [21]. Reports on BRAF mutations are more varied, ranging from 0 to 33 % in LGSCs and 23 % to 48 % in SBTs [17,[21], [22], [23]]. Despite the lower frequency of BRAF mutations, BRAF alterations may be associated with improved prognosis in LGSC [22] and may predict sensitivity to MEK inhibition and/or BRAF-targeted therapies [24,25]. NRAS mutations are observed in ∼10 % of LGSC but not in SBT [20,26,27]. These findings implicate KRAS, BRAF, and NRAS as driver mutations in treatment-recalcitrant LGSC. Mutations in other genes connected to the RAS-MEK-ERK pathway can also be observed, such as NF1, ERBB2, and EIF1AX [5,27]: NF1 is a negative regulators of RAS signaling; HER2 (encoded by ERBB2) is one of the upstream receptor tyrosine kinases that can induce RAS pathway signaling; and EIF1AX cooperates with NRAS in LGSC development [27]. Overall, MAPK pathway alterations are associated with better prognosis in LGSC [14,22]. In contrast to LGSC, mutations in RAS-MEK-ERK pathway genes are uncommon in HGSC, although 10–15 % of HGSC harbor amplifications of KRAS, and up to 20 % of HGSC have focal alterations or gene disruption of NF1, which inhibits RAS by converting it to its inactive form [3,28].

In this review, we discuss different strategies and therapies, both currently in clinical use as well as in clinical trials, that target the RAS-MEK-ERK pathway in LGSC. To date, agents targeting this pathway in LGSC have primarily focused on the inhibition of MEK; however, multiple novel agents developed in the past few years act via inhibition of RAS or targeting of ERK and offer new opportunities for direct inhibition of RAS-MEK-ERK signaling in ovarian cancer [[8], [9], [10]]. Examples of such approaches showing potential benefit in LGSC include the RAF-MEK clamp avutometinib combined with defactinib, MEK inhibitor combinations, and “RAS(ON)” inhibitors. Additionally, as MEK inhibition has become a more commonly used treatment for LGSC, there is a growing need for active therapies for patients whose tumors have progressed on a MEK inhibitor.