Combination therapies targeting CDs with KRASG12C differ in their ability to promote S-IIP target engagement. Combination therapies targeting CDs with.

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Modulation of KRASG12C activity alters ARS-853 target engagement and supports novel therapeutic strategies for targeting KRAS. A, schematic for altering.

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Combination therapies targeting CDs with KRASG12C differ in their ability to promote S-IIP target engagement. Combination therapies targeting CDs with KRASG12C differ in their ability to promote S-IIP target engagement. (A) Chemical structure of the KRASG12C occupancy probe ARS-1323-alkyne. (B) Magnified immunoblots indicating the identities of different bands resulting from electromobility shift after treatment of H358 and MIA PaCa-2 cells with ARS-1323-alkyne (10 μM) and copper-catalyzed click reaction of lysate with TAMRA-N3. (C and D) Representative immunoblots (C) and relative densitometry of upper (KRAS + inhibitor) and lower (KRAS) bands (D) of H358 cells treated with ARS-1323-alkyne (10 μM) simultaneously with DMSO [same as shown in (B) to facilitate comparison], EGF (100 ng/ml), erlotinib (10 μM, EGFRi), SHP099 (10 μM, SHP2i), buparlisib (10 μM, PI3Ki), or palbociclib (10 μM, CDK4/6i) for the times indicated. Lysates were subjected to copper-catalyzed click reaction with TAMRA-N3. Relative densitometry was quantified using upper (KRAS + inhibitor) and lower (KRAS) bands. (E and F) As in (C) and (D), respectively, for MIA PaCa-2 cells. Instead of EGF and erlotinib, MIA PaCa-2 cells were treated with FGF2 (100 ng/ml), AZD4547 (10 μM, FGFRi), and bemcentinib (10 μM, AXLi). Other compounds were administered at the same dose as indicated in (C). Cells in (B) to (F) were grown in 3D spheroid culture. Immunoblots in (B), (C), and (E) are representative of three biological replicates. Data in (D) and (F) represent means of three biological replicates; error bars denote SD. Kevin Lou et al., Sci. Signal. 2019;12:eaaw9450 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works