Ovarian PDX raw growth and sequencing data.

Supplementary Figure and Table Legends

Response to encorafenib and binimetinib of BRAFV600 mutant melanoma PDX models.

Gene expression levels in GIST cell lines.

Supplementary Figure Legends, Table Legends

Gene set enrichment results for the DEG clustering analysis using MSigDB and Metacore gene sets.

Supplementary Figure S2 shows Western blot analysis of A375, WM266-4 and NHEM-TCB cells, colony formation assays for A375 and NHEM-TCB cells, and the effects of ERK1 or ERK2 suppression immediately before or immediately after BRAF-V600E transformation of NHEM-TCB cells.

<p>Candidate biomarkers are not independently prognostic of survival in primary ovarian tumor samples from TCGA.</p>

<p>Supplemental Table 3: List of alternatively spliced genes identified in response to SF3B1 mutant</p>

Mean tumor volume change difference between best monotherapy and each of 9 combinations. Hazard ratio for combination versus independent action simulation PFS.

Supplemental Figure 1. Efficient knockâ€in of DDâ€domain into the endogenous p53 locus by TALENs in HCT116 cells. Supplemental Figure 2. PCR verification of Degronâ€KI clones. Supplemental Figure 3. Immunofluorescence staining of Degronâ€KI cells. Supplemental Figure 4. Quantification of DD tagged proteins in the presence or absence of Shld. Supplemental Figure 5. Highly efficient Degronâ€KI at the endogenous EZH2 locus by CRISPR in HCT116. Supplemental Figure 6. Assessment of the kinetics of DDâ€EZH2 and DDâ€SF3B1 depletion upon Shld withdrawal. Supplemental Figure 7. HCT116 (EZH2 wild type) cells are not sensitive to EZH2 inhibitor EI1. Supplemental Figure 8. RTâ€PCR strategy to identify allele†specific DD tagging of mutant versus wildtype SF3B1. Supplemental Figure 9. UQCC and CRNDE exhibit an altered splice pattern in SF3B1 mutant uveal melanoma cell lines. Supplemental Figure 10. Shld has minimal effects on gene expression of parental Mel202 cells and Mel202 DDâ€mutâ€SF3B1. Supplemental Figure 11. Selective depletion of mutant SF3B1 in Mel202 Degronâ€KI cells reversed the alternative splicing pattern of DYNLL1, SNRPN, TMEM14C, ABCC5, ZDHHC16, RBM18. Supplemental Figure 12. Selective depletion of mutant SF3B1 in Mel202 Degronâ€KI cells by Shld withdrawal predominantly alters 3' splice sites but not 5' splice site selection. Supplemental Figure 13. Confirmation that the DD tag insertion occurred exclusively at the SF3B1 locus in Degronâ€KI engineered Mel202 clones. Supplemental Table 1: Detailed genotypes of ESSâ€1 Degronâ€KI clones. Supplemental Table 2: Detailed genotypes of Mel202 Degronâ€KI clones. depletion using MATS. Supplemental Table 4: Comparison of the alternatively spliced genes identified in this study with genes reported in prior reports (5).

Annotation of primary tumor tissues.

Supplementary Figure S4 shows Western blot analysis and dose-response effects of ERK inhibition in A375 cells expressing inhibitor-resistant ERK2 with or without additional mutations affecting kinase activity or substrate docking.

Supplementary Figure S1. Comparison of drop out phenotypes in MKN45, RKO, HT1080 highlighting selected pan-lethal genes. Supplementary Figure S2. The genes that scored as lethal by both RNAi and CRISPR were strongly enriched for known essential genes classes. Supplementary Figure S3. To identify likely off-target hits the lethality scores of non-expressed genes were examined, as they are expected not to be required for cell viability. Supplementary Figure S4. shRNAs directed towards CDK9 do not show robust protein depletion. Supplementary Figure S5. Additional methods measuring the proliferation effects of individual sgRNA/shRNAs to validate the impact that targeting selected genetic dependencies have on cell viability. Supplementary Figure S6. Correlation analysis displaying features that correlated most significantly with sgRNA potency. Supplementary Figure S7. Effect of relative position within a gene on sgRNA viability effects. Supplementary Figure S8. Non-scoring sgRNA in conserved Pfam domains have a reduced editing efficiency compared to guides with strong viability effects. Supplementary Figure S9. Multiple genomic cuts result in DNA damage induced G2/M cell cycle arrest. Supplementary Figure S10. Multiple genomic cuts lead to an increase in cell death. Supplementary Figure S11. Pie chart demonstrating that the overall contribution of copy number effects in determining essential genes in aneuploid lines is relatively minor.

Ovarian cancer cell lines do not reproduce the clinical association between BRCA loss of function and sensitivity to olaparib, but patient-derived ovarian tumor xenografts do.

List of genes from the DEG clustering analysis.

Figure S1. Cellular phenotypes observed in response to ERK2 overexpression in A-375 cells. Figure S2. No paracrine effect was produced by cells dying due to knockdown of the essential gene PSMA3. Figure S3. A-375 xenograft tumors with ERK2 overexpression displayed necrosis and/or fibrosis. Figure S4. Paradoxical activation triggered by low doses of BRAFi in GR-M augmented the growth suppression caused by ERK2 overexpression. Figure S5. Graphical representations of vector constructs used in this study. Table S1. MSigDB Hallmark pathways that were significantly enriched in genes upregulated after 20 h treatment with doxycycline in A-375 ERK2 cells. Table S2. Transcription factor targets (from MSigDB C3 TFT) for known ERK targets were significantly enriched in genes upregulated after 20 h treatment with doxycycline in A-375 ERK2 cells.

Supplementary Figures - PDF file 1014K, F876L mutation in AR rescues androgen signaling and confers resistance to MDV3100 treatment (Figures S1-S15)

Fig. S1. Summary of EGFR status and sensitivity to erlotinib of NSCLC cell lines used in this study. Fig. S2. Knockdown of CK1α inhibits proliferation of PC9 cells more than proliferation of HCC827 or HCC4006 cells under DMSO treatment. Fig. S3. Performance of individual shRNAs against members of the CK1-family in shRNA screens. Fig. S4. Knockdown of CK1α does not sensitize NSCLC cells to doxorubicin or cisplatin. Fig. S5. Suppression of CK1α attenuates acquired resistance to erlotinib in EGFR-mutant NSCLC cells. Fig. S6. Suppression of CK1α attenuates the outgrowth of drug tolerant persisters (DTPs) to resistant clones and inhibits proliferation of resistant PC9 cells in the presence of erlotinib. Fig. S7. The CK1 inhibitor D4476 can attenuate acquired resistance to erlotinib in NSCLC cell lines. Fig. S8: Knockdown of CK1α does not influence EGFR signaling. Fig. S9: Knockdown of CK1α does not activate WNT-signaling. Fig. S10: Erlotinib treatment activates NF-κB-signaling and CK1α-knockdown decreases expression of NF-κB-target genes. Fig. S11: Inhibition of NF-κB-signaling attenuates resistance to erlotinib while only slightly affecting proliferation in the absence of erlotinib.

Correlation analysis matrix displaying features that correlate most strongly with sgRNA's having off target effects.