Synergistic effect of the inhibitors of RAF/MEK and AXL on KRAS‐mutated ovarian cancer cells with high AXL expression

Abstract

KRAS mutation is frequently seen in a subtype of ovarian cancer categorized as type 1. The KRAS‐MAPK pathway, which is closely involved in type 1 cancer progression, is under the regulation of receptor tyrosine kinases (RTKs). AXL, one of the RTKs, has been reported to be overexpressed in ovarian cancer and contributes to the poor prognosis. However, there is no useful target‐based agent against such gene profiles. We examined the combined effect of the dual RAF/MEK inhibitor CH5126766 and AXL inhibitor R428 on the growth of ovarian cancer HEY‐T30 and OVCAR‐5 cell lines, both of which bear KRAS mutation and express AXL at a high level, using the WST‐8 assay and the colony formation assay. The synergistic effect of the combination was evaluated by the combination index. The apoptotic cells were analyzed by flow cytometry. The expression of apoptotic proteins and the phosphorylation of MAPK and AKT pathway proteins were investigated by western blotting. We found that CH5126766 and R428 suppressed the phosphorylation of ERK and AKT, respectively, and their combination synergistically inhibited the growth of both cell lines with enhancement of apoptosis accompanied by the Bim upregulation. Combined treatment with CH5126766 and R428 is expected as the novel therapeutic option for KRAS‐mutated ovarian cancer with high expression of AXL.

Targeting AXL in NSCLC

“…It remains to be better determined what role AXL plays in necroptosis and PCD in NSCLC. 72 This is consistent with the observation by Zhang et al that the AXL immunohistochemistry pattern was heterogenous even in the acquired resistance settings, consistent with similar findings for other bypass track RTKs, such as the kinase MET. 47 In response to targeted therapeutics, how crosstalk between AXL and other activated RTKs gives rise to tumor heterogeneity is yet to be fully understood.…”

“…Another study reported low AXL level as a predictive biomarker for therapy-induced necroptosis and programmed cell death (PCD) in cancers of diverse origin. 72 The authors found that the dual inhibition blocked both MAPK and PI3K/AKT cell signaling pathways and in result upregulated Bim, a potent molecule that initiates cellular apoptosis. It remains to be better determined what role AXL plays in necroptosis and PCD in NSCLC.…”

Ovarian cancer: Diagnosis and treatment strategies (Review)

“…Currently, the ovarian cancer molecular markers routinely detected in clinical practice are cancer antigen 125 (CA125) ( 12 ), carcinoembryonic antigen (CEA) ( 13 ), human epididymis protein 4 (HE4) ( 14 ), carbohydrate antigen 19-9 (CA19-9) ( 15 ), mesothelin ( 16 ), α-fetoprotein ( 17 ), PARP ( 18 ), FRα ( 19 ), TP53 ( 20 ), HRD ( 21 ), BRCA1/2 ( 22 ) and AXL ( 23 ) ( Table I ); however, the detection of only one of these markers often provides an inaccurate result ( 24 ). CA125 is the most frequently used biomarker in the diagnosis of ovarian cancer ( 25 ), while HE4 was introduced as a biomarker more recently.…”

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

“…A unique Raf/MEK inhibitor, VS-6766/CH5126766, has shown activity in xenograft models of RAS-mutated cancers [111,112]. In parallel, combined treatment with VS-6766/CH5126766 and AXL inhibitor (bemcentinib) has provided a stronger blockage of tumor growth in KRAS-mutant ovarian cancer cells with overexpressed AXL [113]. This allosteric inhibitor prevents the release of MEK from Raf, and thus blocks the subsequent phosphorylation of both MEK and Erk [114].…”