470 Background: Sunitinib is a standard of care for advanced RCC. Despite efforts to identify predictive molecular markers for patient selection, none are available, likely due to multiple resistance mechanisms. Using the Total Cancer Care (TCC) database, which integrates patient clinical, molecular, and biospecimen data, we devised a tumor genomics and transcriptomics experiment to identify differences between RCC patients who derive prolonged clinical benefit from sunitinib versus those who are resistant. Methods: A discovery set of 34 RCC patients treated with sunitinib at the approved regimen were identified in the TCC database (n=16 treated for ≤6 months, having primarily discontinued for reasons other than tolerability; n=18 treated for ≥18 months). Tumor samples were analyzed by whole exome sequencing (WES) and by parallel 400-gene expression profiling. Following gene mutation identification and supervised gene expression analysis, molecular differences between the two groups were identified and tested for potential association with treatment duration. Results: Of the 34 cases identified, 24 remained for analysis following sample QC failure and clinical review (n=10 and 14 treated for ≤6 and ≥18 months, respectively). Gene expression analysis revealed a 37-gene signature associated with treatment duration: MAPK8 (JNK1) was a leading candidate biomarker (Pearson correlation with log [treatment duration]=–0.70; p=0.06 after Bonferroni multiplicity correction). Pathway-based WES analyses identified 25 potential variants of interest, none remaining statistically significant after correction. However, following genome-wide analysis, a single variant in an intronic region of ING3 was statistically associated with treatment duration (p=0.02). Conclusions: Activation of the PI3K/AKT pathway was a marker of resistance to sunitinib. In contrast, activation of the angiogenic, NOTCH, or JAK-STAT pathways was, to some degree, associated with sensitivity to therapy. However, neither VHL alteration nor lack of expression, nor alteration in chromatin-rearrangement genes, was associated with sunitinib treatment duration. These findings require further validation in a larger and independent cohort.
Differential gene expression analysis provides new insights into the molecular basis of iron deficiency stress response in the citrus rootstock Poncirus trifoliata (L.) Raf.
