Preclinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition in low grade serous ovarian cancer.

ABSTRACT

OBJECTIVES: Low-grade-serous-ovarian-carcinoma (LGSOC) is characterized by a high recurrence rate and limited therapeutic options. About one-third of LGSOC contains mutations in MAPK pathway genes such as KRAS/NRAS/BRAF. Avutometinib is a dual RAF/MEK inhibitor while defactinib and VS-4718 are focal-adhesion-kinase-inhibitors (FAKi). We determined the preclinical efficacy of avutometinib±VS-4718 in LGSOC patient-derived-tumor-xenografts (PDX). METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic fingerprint of 3 patient-derived LGSOC (OVA(K)250, PERIT(M)17 and A(PE)148). OVA(K)250 tissue was successfully xenografted as PDX into female CB17/lcrHsd-Prkdc/SCID-mice. Animals were treated with either control, avutometinib, VS-4718, or avutometinib/ VS-4718 once daily five days on and two days off through oral gavage. Mechanistic studies were performed ex vivo using avutometinib±defactinib treated LGSOC tumor samples by western blot. RESULTS: WES results demonstrated wild-type KRAS in all 3 LGSOC. OVA(K)250 PDX showed gain-of-function mutations (GOF) in PTK2 and PTK2B genes, and loss-of-heterozygosity in ADRB2, potentially sensitizing to FAK and RAF/MEK inhibition. The combination of avutometinib/ VS-4718 demonstrated strong tumor-growth inhibition compared to controls starting at day 9 (p < 0.002) in OVA(K)250PDX. By 60 days, mice treated with avutometinib alone and avutometinib/VS-4718 were still alive; compared to median survival of 20 days in control-treated mice and of 35 days in VS-4718-treated mice (p < 0.0001). By western-blot assays exposure of OVA(K)250 to avutometinib, FAKi defactinib and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-ERK. CONCLUSION: Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).