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W4382024771 abstract "Abstract Resistance mechanisms compromise response to single targeted therapies, favoring the idea that combinatorial strategies are key to circumvent this clinical problem. Combinatorial strategies for cancers driven by oncogenic KRAS based on MEK1/2 or KRASG12C inhibitors have so far incorporated abrogation of KRAS proximal effectors involved in oncogenesis or treatment resistance. However, the antitumor effect is highly determined by compensatory mechanisms specifically arising in certain cell types or tumor subgroups. A potential strategy to find drug combinations spanning a large percentage of mutant KRAS lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. Here, integrating a signature-driven drug repurposing approach and a pairwise pharmacological screen, we identify a synergistic drug combination consisting of multityrosine kinase PKC and MEK1/2 inhibitors. The drug combination functions in a genotype specific manner, elicits a cytotoxic response both in vitro and in vivo models, and in part involves inhibition of AURKB. Furthermore, we show that the KRASG12C inhibitor Sotorasib can replace the MEK inhibitor with similar cellular and molecular results, including antitumor effect in a genetically engineered mouse model of lung cancer driven by KRasG12C . Proteome profiling links dysregulation of MYC expression to the effect of PKC inhibitor-based drug combinations. Furthermore, we demonstrate that MYC overexpression functions as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework to nominate drugs entering combinatorial strategies and unveils novel MEK1/2- and KRASG12C-based therapies for lung cancer." @default.
W4382024771 created "2023-06-27" @default.
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W4382024771 date "2023-06-26" @default.
W4382024771 modified "2023-10-18" @default.
W4382024771 title "SIGNATURE-DRIVEN REPURPOSING OF MIDOSTAURIN FOR COMBINATION WITH MEK1/2 AND KRASG12C INHIBITORS IN LUNG CANCER" @default.
W4382024771 cites W1903208781 @default.
W4382024771 cites W2001999652 @default.
W4382024771 cites W2009333774 @default.
W4382024771 cites W2010916968 @default.
W4382024771 cites W2033657262 @default.
W4382024771 cites W2042783729 @default.
W4382024771 cites W2050389860 @default.
W4382024771 cites W2072582894 @default.
W4382024771 cites W2074873270 @default.
W4382024771 cites W2077297619 @default.
W4382024771 cites W2093313266 @default.
W4382024771 cites W2096387850 @default.
W4382024771 cites W2137632714 @default.
W4382024771 cites W2169546036 @default.
W4382024771 cites W2211890826 @default.
W4382024771 cites W2300615341 @default.
W4382024771 cites W2331401984 @default.
W4382024771 cites W2342688693 @default.
W4382024771 cites W2346079527 @default.
W4382024771 cites W2409383155 @default.
W4382024771 cites W2463195069 @default.
W4382024771 cites W2472403803 @default.
W4382024771 cites W2474854223 @default.
W4382024771 cites W2544360569 @default.
W4382024771 cites W2589576518 @default.
W4382024771 cites W2612467560 @default.
W4382024771 cites W2620184199 @default.
W4382024771 cites W2620653306 @default.
W4382024771 cites W2761796839 @default.
W4382024771 cites W2761912328 @default.
W4382024771 cites W2768977980 @default.
W4382024771 cites W2802334782 @default.
W4382024771 cites W2803222616 @default.
W4382024771 cites W2804804971 @default.
W4382024771 cites W2804853604 @default.
W4382024771 cites W2888806113 @default.
W4382024771 cites W2895923466 @default.
W4382024771 cites W2920097475 @default.
W4382024771 cites W2920147611 @default.
W4382024771 cites W2924424204 @default.
W4382024771 cites W2928665623 @default.
W4382024771 cites W2937830908 @default.
W4382024771 cites W2971582034 @default.
W4382024771 cites W2973796265 @default.
W4382024771 cites W2982321167 @default.
W4382024771 cites W2982602983 @default.
W4382024771 cites W2988773550 @default.
W4382024771 cites W2997902533 @default.
W4382024771 cites W2999810289 @default.
W4382024771 cites W3011819195 @default.
W4382024771 cites W3014191583 @default.
W4382024771 cites W3016044799 @default.
W4382024771 cites W3028041439 @default.
W4382024771 cites W3036531306 @default.
W4382024771 cites W3130115867 @default.
W4382024771 cites W3172081492 @default.
W4382024771 cites W3190172544 @default.
W4382024771 cites W3212888956 @default.
W4382024771 cites W4327626369 @default.
W4382024771 doi "https://doi.org/10.21203/rs.3.rs-3100885/v1" @default.
W4382024771 hasPublicationYear "2023" @default.
W4382024771 type Work @default.
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