FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2865458437> ?p ?o ?g. }

• W2865458437 abstract "Mounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade. We examined the molecular and functional effects of single and combined BRAF (dabrafenib), pan-RAF (RAF265), MEK (trametinib) and EGFR/HER2 (lapatinib) inhibition, using Western Blot and conservative isobologram analysis to assess functional synergism, and explored genetic determinants of synergistic interactions. Immunoprecipitation based assays were used to detect the interaction between BRAF and CRAF. The Mann-Whitney U test was used for comparing quantitative variables. Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro. This results in growth inhibitory synergism, both in vitro and in vivo, in the majority (65%) of the cellular models analyzed, encompassing cell lines and patient-derived cancer stem cells and organoids. However, RAS mutational status is not the sole determinant of functional synergism between RAF and MEK inhibitors, as demonstrated in KRAS isogenic tumor cell line models. Moreover, in EGFR-driven contexts, paradoxical MAPK (re)activation in response to selective BRAF inhibition was dependent on EGFR family signaling and could be offset by simultaneous EGFR/HER-2 blockade. Overall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting." @default.
• W2865458437 created "2018-07-19" @default.
• W2865458437 creator A5003507376 @default.
• W2865458437 creator A5011601417 @default.
• W2865458437 creator A5016191595 @default.
• W2865458437 creator A5019167350 @default.
• W2865458437 creator A5023848359 @default.
• W2865458437 creator A5024767391 @default.
• W2865458437 creator A5028581226 @default.
• W2865458437 creator A5029384948 @default.
• W2865458437 creator A5041891737 @default.
• W2865458437 creator A5042097944 @default.
• W2865458437 creator A5042217744 @default.
• W2865458437 creator A5052556729 @default.
• W2865458437 creator A5057975103 @default.
• W2865458437 creator A5065468093 @default.
• W2865458437 creator A5068721926 @default.
• W2865458437 creator A5074574322 @default.
• W2865458437 creator A5080823945 @default.
• W2865458437 creator A5086541444 @default.
• W2865458437 creator A5089822532 @default.
• W2865458437 creator A5091714925 @default.
• W2865458437 date "2018-07-09" @default.
• W2865458437 modified "2023-10-15" @default.
• W2865458437 title "Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models" @default.
• W2865458437 cites W1852944023 @default.
• W2865458437 cites W1922733886 @default.
• W2865458437 cites W1965370740 @default.
• W2865458437 cites W1970527559 @default.
• W2865458437 cites W1986093376 @default.
• W2865458437 cites W1986994161 @default.
• W2865458437 cites W1988729646 @default.
• W2865458437 cites W1990065094 @default.
• W2865458437 cites W1991867384 @default.
• W2865458437 cites W1994599132 @default.
• W2865458437 cites W2004295816 @default.
• W2865458437 cites W2014881369 @default.
• W2865458437 cites W2027737365 @default.
• W2865458437 cites W2041255253 @default.
• W2865458437 cites W2043058822 @default.
• W2865458437 cites W2047195892 @default.
• W2865458437 cites W2050206485 @default.
• W2865458437 cites W2051165598 @default.
• W2865458437 cites W2058142370 @default.
• W2865458437 cites W2058554042 @default.
• W2865458437 cites W2077945404 @default.
• W2865458437 cites W2083607012 @default.
• W2865458437 cites W2091334045 @default.
• W2865458437 cites W2093903659 @default.
• W2865458437 cites W2098272135 @default.
• W2865458437 cites W2099023480 @default.
• W2865458437 cites W2106493454 @default.
• W2865458437 cites W2109031404 @default.
• W2865458437 cites W2119337332 @default.
• W2865458437 cites W2120341265 @default.
• W2865458437 cites W2121389354 @default.
• W2865458437 cites W2121545342 @default.
• W2865458437 cites W2124301770 @default.
• W2865458437 cites W2128059540 @default.
• W2865458437 cites W2133177414 @default.
• W2865458437 cites W2135184154 @default.
• W2865458437 cites W2136989592 @default.
• W2865458437 cites W2138042272 @default.
• W2865458437 cites W2143574474 @default.
• W2865458437 cites W2144708319 @default.
• W2865458437 cites W2149309668 @default.
• W2865458437 cites W2149662085 @default.
• W2865458437 cites W2154196978 @default.
• W2865458437 cites W2157983986 @default.
• W2865458437 cites W2160766792 @default.
• W2865458437 cites W2169761998 @default.
• W2865458437 cites W2338751552 @default.
• W2865458437 cites W2409383155 @default.
• W2865458437 cites W2517722622 @default.
• W2865458437 cites W2564667896 @default.
• W2865458437 cites W2591365298 @default.
• W2865458437 cites W2613470058 @default.
• W2865458437 cites W2785043177 @default.
• W2865458437 cites W2787695357 @default.
• W2865458437 cites W2791410762 @default.
• W2865458437 cites W341385922 @default.
• W2865458437 cites W4295846302 @default.
• W2865458437 doi "https://doi.org/10.1186/s13046-018-0820-5" @default.
• W2865458437 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6038340" @default.
• W2865458437 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29986755" @default.
• W2865458437 hasPublicationYear "2018" @default.
• W2865458437 type Work @default.
• W2865458437 sameAs 2865458437 @default.
• W2865458437 citedByCount "27" @default.
• W2865458437 countsByYear W28654584372018 @default.
• W2865458437 countsByYear W28654584372019 @default.
• W2865458437 countsByYear W28654584372020 @default.
• W2865458437 countsByYear W28654584372021 @default.
• W2865458437 countsByYear W28654584372022 @default.
• W2865458437 countsByYear W28654584372023 @default.
• W2865458437 crossrefType "journal-article" @default.
• W2865458437 hasAuthorship W2865458437A5003507376 @default.
• W2865458437 hasAuthorship W2865458437A5011601417 @default.
• W2865458437 hasAuthorship W2865458437A5016191595 @default.
• W2865458437 hasAuthorship W2865458437A5019167350 @default.

• next