Deregulation of the Ras–mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies1. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes2. Kinase suppressor of Ras (KSR) is a MAPK scaffold3,4,5 that is subject to allosteric regulation through dimerization with RAF6,7. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras–MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.
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We thank K. Shokat, R. Fisher, R. Cagan, S. Aaronson, M. Lazarus, E. Bernstein, and members of the Dar laboratory for comments on the manuscript; A. Maldonado and L. Silber for technical support; and staff at the Advanced Photon Source (Beamline 23-ID-B) for help with X-ray diffraction experiments. The Dar laboratory is supported by innovation awards from the NIH (1DP2CA186570-01) and Damon Runyon-Rachleff Foundation. A.C.D. is a Pew-Stewart Scholar in Cancer Research and Young Investigator of the Pershing-Square Sohn Cancer Research Alliance.
The authors are inventors on a patent application filed by the Icahn School of Medicine at Mount Sinai.
Reviewer Information Nature thanks G. Bollag and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
Extended Data Figure 1 Projection of Ras(G12V) suppressor alleles onto the primary and tertiary structure of KSR.
a, Schematic representation of KSR from Drosophila, Caenorhabditis elegans, and KSR1 or KSR2 from humans. Suppressor mutations within KSR identified from forward genetic screens are highlighted with red stars. Allele names and corresponding mutations are given3,4,5,15. Two alleles in KSR found in the Drosophila screen are shown; one encoding for substitutions in a coil–coil SAM domain (CC-SAM) at the N terminus of Drosophila KSR (S548) and a second mutant in the predicted ATP-binding pocket of the KSR pseudokinase domain (S638). Eight distinct alleles were described in two separate studies conducted in C. elegans. The vast majority of the mutants localize to the pseudokinase domain of KSR and in particular ATP-contact residues (yellow). Residues highlighted in red and shown in the lower panel correspond to the human KSR2 residue equivalents of suppressor mutations found in Drosophila and C. elegans orthologues. b, KSR is a scaffold for the Ras–MAPK signalling pathway. Phosphorylation of MEK1/2 at Ser218 and Ser222 by RAF, or ERK1/2 via phosphorylation at Thr202 and Tyr204 by MEK, are key events in signalling through the Ras–MAPK signalling pathway. c, Purification of the KSR2–MEK1 complex from insect cells. The KSR2 pseudokinase domain (KSR2(KD)) and MEK1 were co-expressed using the SF21 insect cell system. Lysis was performed by one freeze–thaw and sonication. Lysates were incubated with cobalt resin for 2 h and KSR2(KD)–MEK1 was eluted using a high-imidazole buffer. Eluate was then incubated with tomato etch virus (TEV) protease and λ-phosphatase overnight. The mixture was then applied to an ion-exchange column (Sp-HP) to separate stoichiometric KSR2–MEK1 complexes from free MEK1 and TEV. Fractions containing KSR2–MEK1 were applied to a gel-filtration column for final purification. d, Schematic of the ATPbiotin probe-labelling assay on KSR2–MEK1 complexes and screen for inhibitors. e, ATPbiotin directly labels KSR2 and MEK1 within purified complexes. Deconvoluted mass spectrum for KSR2–MEK1 complexes incubated with ATPbiotin. KSR2 and MEK1 spectra are included in the top and bottom panels, respectively. f, Graphical representation for ATPbiotin probe-labelling of KSR2–MEK1 complexes in the presence of increasing free ATP as shown in Fig. 1b. Corresponding IC50 values listed for both KSR2 and MEK1.
a, Chemical structures of APS-2-79 and APS-3-77 with respective IC50 values (mean ± s.d.; n = 2 biological replicates) for KSR2. b, Representative western blot images of in vitro ATPbiotin competition assays using recombinant MAPK family member proteins. Probe-labelling of the indicated kinases were measured in the presence of increasing concentrations of APS-2-79, APS-3-77, or a positive control compound. For CRAF, BRAF, and BRAF(V600E), the positive control was dabrafenib; for MEK1, the ATP-competitive inhibitor termed Wyeth-2b (ref. 28); and for ERK, SCH722984 (ref. 29). The listed IC50 values include mean ± s.d. based on two biological replicates. c, APS-3-77 and APS-2-79 share partially overlapping kinome-wide inhibitory profiles. The graph shows the percentage of inhibition of APS-2-79 and APS-3-77 (both at 1 μM) against 246 kinases. The raw data for this graph is in Supplementary Table 1. d, Inset showing the 25 kinases most inhibited by APS-2-79 and APS-3-77. Kinases with near-equal sensitivity to these inhibitors as measured here include YES1, ERBB4, and FGR; variable sensitivity kinases include CSK, HCK, and MERTK.
a, Schematic of the RAF phosphorylation assay of free KSR2–MEK1 and MEK1. b, Phosphorylation of the indicated concentrations of MEK1 and the KSR2–MEK1 complex by BRAF (200 nM) in the presence of 1 mM ATP. Representative blots for phospho-MEK (top; as detected using a MEK1/2(pS218/pS222) antibody) and total MEK (tMEK; bottom) are shown. c, Plots of pMEK versus time (seconds) at various concentrations of MEK1 and the KSR2–MEK1 complex. Bands were quantified and the phospho-MEK signal normalized relative to lane 20 in both panels. Data points of two biological replicates are included along each line. The rate of MEK phosphorylation (Kobs; pMEK per second; far right) are represented in bar graphs and are derived from the linear phase of the plots in the left hand panels. Bars represent mean of two biological replicates; values for each replicate are shown as points. d, Rates of BRAF (left) and CRAF (right) phosphorylation of the indicated MEK complexes (KSR2–MEK1; KSR2(A690F)–MEK1; and free MEK). Bars represent mean of two biological replicates; values for each replicate are shown as points. e–g, APS-2-79 inhibits BRAF and CRAF phosphorylation of MEK in a KSR-dependent manner. Phosphorylation of 500-nM KSR2–MEK1 (e), or KSR2(A690F)–MEK1 (f), and MEK1 (g) by BRAF (200 nM) or CRAF (10 nM) in the presence of 1-mM ATP and the indicated inhibitors. Representative western blots of phospho-MEK (as detected using a MEK1/2pS218/pS222 antibody) are shown. Bars represent mean of two biological replicates; individual data points of each replicate are shown.
Extended Data Figure 4 APS-2-79 activity is not dependent on KSR phosphorylation sites in MEK or direct RAF inhibition.
a, APS-2-79 does not affect BRAF(V600E)-induced MAPK activation in cells. BRAF(V600E)–Flag was expressed for 24 h in 293H cells. Cells were then treated for 2 h with DMSO or 5 μM of either APS-2-79, APS-3-77, or dabrafenib before collection and western blot analysis of phosphorylated MEK (MEK1/2(pSer218/pSer222)) and ERK (ERK1/2(pT202/pY204)). b, Removal of putative KSR phosphorylation sites in MEK (MEK(AAAA); S18A, T23A, S24A, S72A; ref. 7) neither hinders KSR-dependent MAPK signalling, nor the activity of APS-2-79. Co-expression of full-length KSR–Flag and wild-type MEK1–GFP or MEK(AAAA)–GFP leads to enhanced MAPK signalling within 293H cells as visualized by immunoblotting for phosphorylated MEK (MEK1/2(pSer218/pSer222)) and ERK (ERK1/2(pT202/pY204)). APS-2-79 impedes KSR-stimulated MAPK signalling within cells through wild-type and MEK(AAAA) equally. Bars and error bars indicate pMEK and pERK intensity and standard deviations, respectively. Signals were normalized relative to lane 5. Error bars indicate the mean ± s.d. (n = 3 biological replicates). ***P < 0.0005 by two-tailed unpaired t-testing. c, The dimer-deficient KSR(R718H) mutant, relative to wild-type KSR, is compromised in MEK-inhibitor-induced feedback. 293H cells were co-transfected with MEK–GFP and KSR–Flag or KSR(R718H)–Flag for 24 h and then treated with increasing concentrations of trametinib (range of 0.13 to 100 nM; threefold dilutions) for an additional 48 h. Cells were collected and analysed by western blot. d, Phospho-AMPK remains unchanged in HCT116 cells upon co-treatment with APS-2-79 and trametinib. HCT116 cells were treated with APS-2-79 and/or trametinib for 48 h. Phospho-AMPK (top), phospho-ERK(pERK), and total MEK (bottom) western blots are shown.
a, Assembly of the KSR2–MEK1 heterodimer bound to APS-2-79. A crystal-packing two-fold symmetry axis of the asymmetric unit containing a single KSR2–MEK1 complex produces the heterotetramer. KSR2 bound to APS-2-79 is coloured green, and MEK1 is coloured red. The activation segments of KSR2 and MEK1 are coloured orange and white, respectively. The ‘induced lock’ (residues 809 to 814) within KSR2 is highlighted as orange, red and blue spheres. b, Assembly of the KSR2–MEK1 heterodimer bound to ATP as reported ref. 7 (PDB code: 2Y4I). A crystallographic two-fold rotation axis produces the heterotetramer. r.m.s. deviation between the heterodimer and heterotetramers, respectively, of the ATP- and APS-2-79-bound KSR2–MEK1 complexes are listed below. c, A model for APS-2-79 function as a KSR-targeted antagonist of MAPK signalling. APS-2-79 shifts the equilibrium of KSR2–MEK1 complexes so to populate the OFF state (left), and thereby antagonizes RAF dimerization and subsequent phosphorylation of KSR-bound MEK (far right). The model for RAF dimerization and MEK phosphorylation are adapted from ref. 7. In this model, the role of RAFcat may be fulfilled by multiple active RAF-family kinases, such as C-RAF, bound within homo- or heterodimers of RAF–RAF or KSR–RAF, respectively.
Extended Data Figure 6 The APS-2-79 binding site within KSR2 and possible basis for KSR over RAF selectivity.
a, APS-2-79 and ATP are overlaid in the KSR2 and MEK1 active sites, respectively. ATP was shown here to emphasize the MEK active site, but ATP was not included in the final model. Positive (blue) and negative (red) Fo − Fc electron density maps, calculated before modelling of APS-2-79, are contoured at 3.5σ. Strong-positive-difference density within KSR2 supported modelling of APS-2-79 bound to KSR2 within the KSR2–MEK1 complex. b, Electron density map (blue mesh) for APS-2-79 (sticks) contoured at 4.5σ. Map represents positive difference density within the KSR2 active site before modelling of APS-2-79. c, Superposition of KSR2 (ATP- and APS-2-79-bound) with BRAF monomer (PDB code: 4W05) and BRAF dimer (PDB code: 3C4C) co-crystal structures reveals the possible bases for selectivity of APS-2-79 for KSR over RAF proteins. Residues within the APS-2-79 binding pocket that diverge between KSR and RAF proteins, but which are highly conserved within both sub-families are indicated with arrows. Thr802 in KSR2, which is universally a Gly residue in all active RAF homologues, and also Phe516 and Phe793 in KSR2, which adopt distinct orientations from the equivalent Phe residues in RAF kinases, directly contact the biphenyl ether motif in APS-2-79. The T802G substitution, as well as the positional differences of the above-mentioned aromatic residues, would be predicted to reduce binding of active RAFs with APS-2-79. Another interaction that is probably favoured in KSR includes the contact mediated by the epsilon nitrogen of Arg692 with the –O- linker of the biphenyl motif; the placement of Arg692 is stabilized by Asp803 of the DFG motif. In RAF, the Arg-to-Lys substitution (Lys483 in subdomain II of BRAF), lacks the equivalent nitrogens to bond with both the –O- linker in APS-2-79 and the aspartate of the DFG motif. d, Positive (blue) and negative (red) Fo − Fc electron density map contoured at ± 2.5σ, before modelling of residues I809 to Q814 in KSR2, is shown. e, Sequence alignment of KSR and RAF proteins. Arrows highlight APS-2-79 contact residues.
Representative western blot images of in vitro ATPbiotin competition assays using recombinant KSR2–MEK1 and analogues reported in this study. Chemical structures are shown adjacent to assay blots. IC50 values (mean ± s.d.; n = 2 biological replicates) against ATPbiotin probe-labelling of KSR2 are listed below blots. Line graphs include data points from two biological replicates.
Extended Data Figure 8 Bio-layer inferometry binding data between BRAF and free MEK1 or the KSR2–MEK1 complex.
a, Mapping of residues with a r.m.s. deviation of greater than 2.0 Angstrom between the ATP- and APS-2-79-bound states of KSR2–MEK1 (right, blue), highlights alterations at contact residues Trp685 and His686 within the KSR–KSR homodimer (left, yellow) and KSR–RAF heterodimer (middle, orange) interfaces. b, Movement of Trp685–His686 within KSR2 between the ATP- and APS-2-79-bound states. A single protomer of KSR2 in the ATP-bound state (yellow), and both protomers (green and cyan) of the KSR2 dimer within the APS-2-79-bound state, are shown. Negative density around W685 and His686 in early-stage maps supported the conformational change in this loop between the ATP- and APS-2-79-bound states. c, The negative control compound APS-3-77 (25 μM) does not impact assembly of BRAF(F667E) and KSR2–MEK1. These assays were performed identically to the experiments in Fig. 3b–g. Coloured curves indicate dose ranges of KSR2–MEK1 or MEK1 from 625 nM to 10 μM in the presence or absence of the indicated compounds. In all plots, association occurred from 0 to 660 s, and dissociation was monitored thereafter up to 1500 s. d–e, Biolayer inferometry of wild-type BRAF with MEK1 and KSR2–MEK1 in the presence of DMSO and 25 μM APS-2-79. These assays were performed identically to the experiments in Fig. 3b–g. Coloured curves indicate dose ranges of KSR2–MEK1 or MEK1 from 625 nM to 10 μM in the presence or absence of the indicated compounds. In all plots, association occurred from 0 to 660 s, and dissociation was monitored thereafter up to 1500 s. f, Table summary of BLI data in this figure and Fig. 3b–h. Kd, Kon, and Koff values represent the mean and s.e.m. measurements derived from global fitting of 5 binding curves. χ2 and R2 describe experimental and model data correlations; <3 and above 0.95, respectively, indicate good fits.
a, Average Bliss score of the combination of trametinib, binimetinib, PD0325901, or AZD6244 with APS-2-79 in the Ras-mutant cell lines HCT116 and A549 versus the RAF-mutant cell lines A375 and SK-MEL-239. Full combination matrices of APS-2-79 (range: 100 nM to 3 μM in threefold dilutions) with trametinib (range: 0.01–100 nM in threefold dilutions), binimetinib (range: 0.1–10 μM in threefold dilutions), PD0325901 (range: 0.1–10 μM in threefold dilutions), and AZD6244 (range: 0.1–10 μM in threefold dilutions). Bars represent the mean Bliss scores calculated from two biological replicates of the depicted concentration matrices; points represent each calculated score. b, Average Bliss scores of APS-2-79 or APS-3-77 in combination with trametinib in RAF-mutant, RAS-mutant cell lines. SK-MEL-2 and HepG2 are N-Ras-mutant cell lines, and MEWO is a NF1-mutant cell line. Bars represent the mean Bliss scores calculated from two biological replicates of the depicted concentration matrices; points represent each calculated score. c, Complete cell viability analysis of APS-2-79 (range: 100–3,000 nM in threefold dilutions) plus trametinib (range: 0.01–100 nM in threefold dilution) over a full concentration matrix in the Ras-mutant LOVO, CALU-6, SW620, SK-MEL-2, and HEPG2 cell lines, the RAF-mutant COLO-205, H2087, and SW1417 cells, and the NF1-mutant MEWO cell line. Numbers listed within synergy matrices represent percentage of growth inhibition relative to DMSO control and are the mean of two biological replicates. Bliss scores represent the mean calculated from two biological replicates of the depicted concentration matrices.
Extended Data Figure 10 APS-2-79 synergizes with trametinib specifically in Ras-mutant cells compared to the HER-family and SRC-family inhibitors lapatinib and sarcatinib.
a, Chemical structures of APS-2-79 and quinazoline-containing kinase inhibitors sarcatinib and lapatinib. The primary targets for sarcatinib and lapatinib are c-Src and Her2, respectively30. IC50 values against ATPbiotin probe-labelling of KSR2 are listed below structures. b, Bliss score analysis of HCT-116, A549, A375, and SK-MEL-239 cells treated with APS-2-79, sarcatinib, or lapatinib (range: 100–3,000 in threefold dilutions) in combination with trametinib (range: 0.01–100 in threefold dilution). Bars represent the mean Bliss scores calculated from two biological replicates; points represent each calculated score. c, Absolute Bliss score of the indicated drugs in combination with trametinib in Ras-mutant relative to RAF-mutant cell lines demonstrates selective synergy in Ras-mutant cell lines for APS-2-79 compared to sarcatinib and lapatinib. d, log of the combination index graphs of APS-2-79 in combination with trametinib in HCT-116 versus SK-MEL-239 cells as compared to the fractional effect. Negative combination index over a broad fractional effect range within HCT-116, but not SK-MEL-239, indicates strong synergy.
This file contains Supplementary Methods and additional references. (PDF 1511 kb)
This file contains the uncropped blots for Figures 1,4 and Extended Data Figures 2, 3, 4 and 7 (Supplementary Figures 1-8) and Supplementary Tables 1-3. (PDF 12419 kb)
This file contains the Source Data for Bliss Score Calculations of all inhibitor combinations and cell lines tested in the manuscript. (XLSX 327 kb)
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Dhawan, N., Scopton, A. & Dar, A. Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling. Nature 537, 112–116 (2016). https://doi.org/10.1038/nature19327
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