Imaging markers of response to combined BRAF and MEK inhibition in BRAF mutated vemurafenib-sensitive and resistant melanomas

A majority of patients with a V600x melanoma respond quickly to BRAF/MEK inhibition (BRAFi/MEKi) and have an obvious clinical benefit. Nearly all the patients after this initial phase will develop resistance. Therefore, non-invasive early markers of response/non-response are needed in order to identify those patients who, due to intrinsic or acquired resistance, do not respond to treatment and would be eligible for alternative treatments. The aim of this study was to investigate the value of magnetic resonance spectroscopy ((1)H-MRS) of choline and diffusion-weighted magnetic resonance imaging (DW-MRI) as early markers of response to BRAF inhibition (BRAFi) with vemurafenib alone or in combination with MEK inhibition (MEKi) with trametinib, in BRAFi-sensitive and BRAFi-resistant melanoma xenografts. Tumor response was significantly improved by the combination of BRAFi and MEKi, compared to BRAFi alone, only in sensitive xenografts; thus indicating that vemurafenib-resistant A375R xenografts were cross-resistant to the inhibition of MEK, as confirmed by immunohistochemistry analysis for phosphorylated ERK. In vivo (1)H-MRS showed that in sensitive melanoma xenografts, a significant blockage of ERK phosphorylation, but not a decrease in cell proliferation, was required to affect total choline (tCho) levels, thus suggesting that tCho could serve as a pharmacodynamic (PD) marker for agents targeting the MAPK cascade. In addition, early effects of the combination therapy on tumor cellularity could be detected via DW-MRI. In particular, skewness and kurtosis of the apparent diffusion coefficient (ADC) distribution may be useful to detect changes in the diffusional heterogeneity that might not affect the global ADC value.