Novel Small Molecule MEK Inhibitor URML-3881 Enhances Cisplatin Sensitivity in Clear Cell Ovarian Cancer

Abstract

Advanced clear cell ovarian cancer (CCOC) is a highly fatal malignancy with a scarcity of effective treatment options. CCOC is inherently chemotherapy resistance, but the exact mechanism of this resistance has yet to be established. Prosurvival signaling, such as through the MAPK cascade, is one way in which cancer cells can evade chemotherapy. We have determined that CCOC exhibits baseline elevated levels of MAPK activity, which increase further upon cisplatin exposure. We have developed a novel MEK inhibitor, URML-3881, to test the effect of MAPK inhibition in CCOC. URML-3881 was found to reduce in vitro CCOC viability through apoptosis and proliferation inhibition, yet it failed to induce in vivo tumor regression. Similarly, cisplatin alone had minimal impact on tumor growth, but remarkably, the combination of MEK inhibition and cisplatin led to a significant and prolonged tumor regression. These studies confirm that the combination of MEK inhibition with URML-3881 and cisplatin is superior to either agent alone in CCOC. Our data support the design of future preclinical and clinical studies into the combination of MEK inhibition and platinum-based chemotherapy as a treatment strategy for CCOC.

Unique Molecular Features in High-Risk Histology Endometrial Cancers

“…However, unlike physiologically normal stem cells, cancer stems cells have a higher mutational burden, causing them to have increased dysfunction that may be related to their highly invasive properties. This dysfunctional signaling commonly occurs in growth signaling pathways frequently identified in cancers (i.e., JAK/STAT, AKT, WNT, NFκB ), with particular activation in cells selected for “stemness” and may be responsible for the stem cell’s inadequate response to standard therapies [33,34]. Since cancer stem cells are less responsive to conventional therapies than the non-stem cell population within tumors, they are thought to survive following treatment, leading to cancer progression or recurrence.…”

Optimized Transcriptional Signature for Evaluation of MEK/ERK Pathway Baseline Activity and Long-Term Modulations in Ovarian Cancer

“…Adding MEK/ERK inhibitors to various chemotherapeutic agents [ 47 ], including ALDH1A inhibitor [ 18 ] and Src inhibitor [ 22 ], has been suggested as a way to overcome ovarian cancer therapy resistance. What is even more important is that a number of recent studies reported that MEK inhibition therapy may sensitize ovarian cancer cells to the cytotoxic action of platinum drugs both in vitro and in vivo [ 45 , 48 , 49 ]. We did not observe significant associations between COMS genes expression and initial platinum sensitivity in clinical cases from TCGA.…”

MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives

“…These studies support the notion that URML-3881 and cisplatin in combination with MEK inhibition work better for CCOC than either drug alone. 102 WX-554 is a MEK1/2 inhibitor that is currently undergoing preliminary human research. WX-554 was well tolerated, as demonstrated by pharmacokinetic and pharmacodynamic data for phase I investigation, and a phase II fixed dose of 75 mg twice weekly was advised.…”