KEY TAKEAWAYS
- The study aimed to investigate the efficacy of avutometinib with FAK inhibitors in high-grade EAC.
- Researchers observed that avutometinib and defactinib show promise for high-grade EAC, warranting clinical trials.
High-grade endometrial cancers (EAC) are aggressive tumors associated with a high risk of progression following treatment. Given that EAC often contains mutations in the RAS/MAPK pathways, this study assessed the preclinical efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718.
Tobias Max Philipp Hartwich and the team aimed to assess the potential of these drug combinations for treating high-grade EAC.
They performed an inclusive analysis using whole-exome sequencing (WES) to map the genetic landscape of 5 primary EAC cell lines. The in vitro efficacy of avutometinib and defactinib, both individually and in combination, was assessed through cell viability, cell cycle, and cytotoxicity assays. Mechanistic insights were obtained via Western blot assays. Additionally, in vivo, experiments were conducted using UTE10 engrafted mice, which were treated with vehicle, avutometinib, VS-4718, or their combination through oral gavage.
About the results, WES revealed that multiple EAC cell lines harbored genetic derangements in the RAS/MAPK pathway, including KRAS, PTEN, PIK3CA, BRAF, and ARID1A, which may sensitize these cells to FAK and RAF/MEK inhibition. All 5 EAC cell lines exhibited in vitro sensitivity to either FAK and/or RAF/MEK inhibition.
The western blot assays showed that exposure to defactinib, avutometinib, and their combination resulted in decreased phosphorylated FAK (p-FAK), as well as reduced p-MEK and p-ERK levels. In vivo, the combination of avutometinib and VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatments and controls, with significant differences observed starting at Day 9 (P < 0.02 and P < 0.04) in UTE10 xenografts.
The study concluded that avutometinib, defactinib, and, to a larger extent, their combinations exhibited promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical findings support the potential for clinical evaluation of this combination in patients with high-grade EAC.
This study was funded by the NIH U01 CA176067-01A1, the Deborah Bunn Alley Foundation, the Domenic Cicchetti Foundation, the Discovery to Cure Foundation, and the Guido Berlucchi Foundation to A.D.S.
Source: https://pubmed.ncbi.nlm.nih.gov/39240189/
Hartwich TMP, Mansolf M, Demirkiran C, et al. (2024). “Preclinical evaluation of avutometinib and defactinib in high-grade endometrioid endometrial cancer.” Cancer Med. 2024;13(17):e70210. doi:10.1002/cam4.70210
