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

Gynecol Oncol. 2024 Apr:183:133-140. doi: 10.1016/j.ygyno.2024.01.028. Epub 2024 Mar 15.

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).

Keywords: Avutometinib; Defactinib; FAK inhibitor; Low-grade serous ovarian cancer; MEK inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Benzamides
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / pathology
  • Diphenylamine / analogs & derivatives
  • Exome Sequencing
  • Female
  • Focal Adhesion Kinase 1* / antagonists & inhibitors
  • Focal Adhesion Kinase 1* / genetics
  • Focal Adhesion Kinase 1* / metabolism
  • Humans
  • Mice
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazines
  • Sulfonamides
  • Xenograft Model Antitumor Assays*

Substances

  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Protein Kinase Inhibitors
  • defactinib
  • N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
  • Benzamides
  • Diphenylamine
  • Pyrazines
  • Sulfonamides

Associated data

  • ClinicalTrials.gov/NCT04625270