Abemaciclib (µM) LY (µM)

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Abemaciclib (µM) LY3009120 (µM) 0 0.005 0.01 0.02 0.05 0.1 0.2 0.25 0 0.005 0.01 0.02 0.05 0.1 0.2 0.25 0.5 Abemaciclib (µM) 1 2 4 Supplementary Figure S1. RAF inhibition by LY3009120 sensitizes KRAS mutant cancer cells to abemaciclib. HCT116 cells were in treated for 5 days with increasing concentrations of LY3009120 and abemaciclib. At the end of the experiment, cells were fixed and stained with crystal violet solution.

A Calu-6 (KRAS Q61K) B HCT116 (KRAS G13D) C A375 (BRAF V600E) D SK-MEL 30 (NRAS Q61K) E HT-29 (BRAF V600E) Supplementary Figure S2. Heatmaps of LY3009120 and abemaciclib combination in different tumor cell lines. Plots show the observed percent inhibition minus the expected additive response (EAR). The EAR is estimated using Bliss Independence for each combination dose. The numbers on the left side are concentrations of abemaciclib, and the numbers on top are concentrations of LY3009120. The red color indicates additive or synergistic effects, and the darker the red indicates the more synergistic effect by combination.

A B APC D-Cyclin activation Geometric Mean Abs. IC50 (mM) Geometric Mean Abs. IC50 (mM) Cell Lines Cell Lines C D RB1 PI3K pathway mutations Geometric Mean Abs. IC50 (mM) Geometric Mean Abs. IC50 (mM) Cell Lines Cell Lines E CDKN2A Geometric Mean Abs. IC50 (mM) Cell Lines Supplemental Figure S3. In vitro activities of LY3009120 and abemaciclib combination in cancer cell screen panel (CCSP) and their sensitivity association with APC mutations (A), D-cyclin activation (B), RB mutations (C), PI3K pathway mutations (D) and CDKN2A mutations (E). Green color indicates cell lines with mutation or alteration of specified gene or pathway in individual panels.

A. Calu-6 (KRAS Q61K) B. HCT116 (KRAS G13D) C. SKMel-30 (NRAS Q61K) D. A375 (BRAF V600E) E. WM-266-4 (BRAF V600E ) F. HT-29 (BRAF V600E) G. HCT116 (intermittent dosing) Supplemental Figure S4. Body weight changes of rats bearing the indicated xenograft tumors treated with LY3009120, abemaciclib or their combination from the same studies shown in Figure 3.

A. SK-Mel30 Ctrl pan-RAFi CDK4/6i Combo %G1= 40.02 %S = 45.85 %G2/M = 14.13 %Debris = 14.46 %G1= 55.16 %S = 32.91 %G2/M = 11.94 %Debris = 18.76 %G1= 62.38 %S = 23.34 %G2/M = 14.28 %Debris = 13.26 %G1= 74.94 %S = 11.85 %G2/M = 13.21 %Debris = 13.30 B. A375. %G1= 67.07 %S = 25.49 %G2/M = 7.44 %Debris: 2.29 %G1= 71.75 %S = 19.57 %G2/M = 8.67 %Debris: 1.49 %G1= 75.73 %S = 14.80 %G2/M = 9.47 %Debris: 3.71 %G1= 91.31 %S = 2.09 %G2/M = 6.61 %Debris: 2.13 Supplementary Figure S5. Combinatory treatment targeting Raf and CDK4/6 enhances cell cycle G1 arrest, A, cell cycle analysis of SK-Mel-30 cells treated with DMSO, LY3009120 (0.01 µM), abemaciclib (0.5 µM), or the combination for 48 h. B, cell cycle analysis of A375 cells treated with DMSO, LY3009120 (0.01 µM), abemaciclib (1 µM), or the combination for 72 h. After treatment, cells were subjected to PI staining and subsequent flow cytometry analysis for cell cycle distribution. Dead cells are indicated as debris. Representative histograms were shown from at least two independent experiments. Also see Figure 4.

Supplementary Table S1: Mutational status of cancer cell lines tested in this study Genetic mutation Cancer type BRAF KRAS NRAS TP53 CDKN2A PIK3CA Calu-6 lung WT Q61K R196* HCT116 colon G13D del31 H1047R HT-29 V600E R273H P449T SKMel-30 skin T284fs*21 P114L A375 E61*, E69*, W66R WM-266-4