Design and outcome details for each AZD8835 in vivo efficacy study.

PDF file - 37K, Characteristics of the 4 CRC datasets used in training (KFSYSCC) and validation of the RAS model.

PDF file - 35K, Data sets used for evaluation of the colorectal RAS model, and reported AUC in classification of KRAS mutant from wild-type samples.

PDF file - 35K, Characteristics of the 2 metastatic CRC datasets used for evaluation of prediction of PFS.

Combination of AZD8835 with mTOR kinase inhibitor AZD2014 (+/- fulvestrant) increases anti-tumor efficacy in breast xenografts

Body Weight time-courses for AZD8835 combination efficacy studies.

Tumor cell line panel composition and growth inhibition sensitivity (GI50) to AZD8835.

AZD8835 combination with SERDs (fulvestrant or AZD9496) results in tumor regression in mutant PIK3CA, ER+ breast xenografts.

PDF file - 219K, Supplemental Figure 1. A We evaluated 4 "RAS" signatures across 4 CRC data sets to assess their ability to discriminate KRAS mutant samples from KRAS wild-type. Supplemental Figure 2. The lower observed RIS of KRAS codon 13 mutated samples relative to KRAS codon 12 mutated samples may be a result of the imbalanced distribution of these mutations in the training data. Supplemental Figure 3. RIS distribution by mutation of KRAS, BRAF, NRAS mutations, and wild-type. Supplemental Figure 4. RAS index score (RIS) for PIK3CA mutant samples by exon in the TCGA CRC cohort. Supplemental Figure 5. Distribution of RIS for the subset of colorectal samples (n=19) within the Cancer Cell Line Encylopedia (CCLE), separated by KRAS codon, BRAF V600E, PIK3CA (KRAS/BRAF wild-type), or wild-type (no KRAS/BRAF/PIK3CA) mutation. Supplemental Figure 6. In the mouse early passage cohort (n=26), our RAS model outperforms the KRAS/BRAF mutation model (p=0.06 vs p > .1, respectively). Supplemental Figure 7. Association of RIS and cetuximab response for metastatic colorectal patients (Khambata-Ford, et al.) Patients annotated according to treatment response: Progressive Disease (PD), Stable Disease (SD) and Partial Response (PR) as well as KRAS mutation status.

Contains Supplementary Material and Methods, Suuplementary Table & Figure Legends and Supplementary References.

PDF file - 32K, PFS analysis within the French cohort.

Full details on antibodies used in AZD8835 studies.

Details on PK / PD / efficacy modeling in BT474 xenograft model

Proliferation and mechansitic assays in mutant PIK3CA, ER+ breast cell lines studying combinations of AZD8835 with SERDs, palbociclib or AZD2014.

Timecourse of PI3K pathway inhibition in MCF7 cells illustrating pathway reactivation over time.

PDF file - 33K, Univariate analysis.

PDF file - 43K, Top RAS model genes.

Statistical analysis comparing efficacy between study arms of AZD8835 in vivo combination studies.

Details on cell lines used in AZD8835 selectivity profiling and efficacy studies.

AZD8835 induced apoptosis in MCF7 measured by gamma-H2AX and PARP cleavage.