Abstract
SummaryDespite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.
Highlights
Malignant melanoma has very poor survival rates (Balch et al, 2009) despite being at the forefront of personalized medicine (Lau et al, 2016)
MAPK Regulates Myosin II Activity in Melanoma To gain unbiased insight into molecular changes in melanoma cells after MAPK inhibitors (MAPKi), we analyzed the phosphoproteome of BRAFV600E A375 melanoma cells early (24 h) on MEK inhibitor (MEKi) (GSK1120212 trametinib and PD184352) treatment (Figure 1A; Table S1)
Using MetaCore Pathway enrichment analysis, we found that cytoskeletal remodeling and Rho GTPase signaling are top processes changing early on treatment (Figure 1A; Tables S1 and S2)
Summary
Malignant melanoma has very poor survival rates (Balch et al, 2009) despite being at the forefront of personalized medicine (Lau et al, 2016). Mutant BRAF (V600) is the most common oncogene in melanoma (Davies et al, 2002), driving proliferation, survival, and tumor progression by hyper-activating MEK and ERK kinases (Gray-Schopfer et al, 2007). This led to BRAFV600E inhibitors (BRAFi) development (Chapman et al, 2011; Flaherty et al, 2010; Zhang, 2015). Most patients had partial responses and disease progressed due to acquired resistance (Larkin et al, 2014; Robert et al, 2015; Zhang, 2015).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
