Analysis of delay in adjuvant chemotherapy in locally advanced rectal cancer

BackgroundAdjuvant chemotherapy (AC) after neoadjuvant chemoradiation and surgical resection has been the standard of care for locally advanced rectal cancer. However, there are no evidence-based guidelines regarding the optimal timing of AC for rectal cancer. The objective of this study was to evaluate the effect of AC timing on overall survival for rectal cancer.MethodsThe National Cancer Database (NCDB) from 2004 to 2016 was queried for primary clinical stage II or III rectal cancer patients who had undergone neoadjuvant chemoradiation followed by surgery and AC. Patients were grouped based on AC initiation: early ≤ 4 weeks, intermediate 4-8 weeks, and delayed ≥ 8 weeks. The primary outcome was overall survival.ResultsWe identified 8722 patients, of which 905 (10.4%) received early AC, 4621 (53.0%) intermediate AC, and 3196 (36.6%) delayed AC. Pathological lymph-node metastasis (ypN +) was positive in 73% of early AC, 74% intermediate AC, and 63% delayed AC (p < 0.05). The 5-year survival probability was 71.1% (95% CI 68-74%) for early AC, 73.2% (95% CI 72-75%) intermediate AC, and 65.8% (95% CI 64-68%) delayed AC (p < 0.001). Using Cox proportional hazard modeling, patients undergoing delayed AC had an associated decreased survival compared to patients receiving early AC (HR 1.18; 95% CI 1.028-1.353, p = 0.018) or intermediate AC (HR 1.28; 95% CI 1.179-1.395, p < 0.01).ConclusionsDelay in AC administration may be associated with decreased 5-year survival. Compared to early or intermediate AC, patients in the delayed AC group were observed to have increased risk of death, despite having lower proportions with ypN + disease. Patients with higher socioeconomic and education status were more likely to receive early chemotherapy

Characterization and structural determination of a new anti-MET function-blocking antibody with binding epitope distinct from the ligand binding domain

The growth and motility factor Hepatocyte Growth Factor/Scatter Factor (HGF/SF) and its receptor, the product of the MET proto-oncogene, promote invasion and metastasis of tumor cells and have been considered potential targets for cancer therapy. We generated a new Met-blocking antibody which binds outside the ligand-binding site, and determined the crystal structure of the Fab in complex with its target, which identifies the binding site as the Met Ig1 domain. The antibody, 107_A07, inhibited HGF/SF-induced cell migration and proliferation in vitro and inhibited growth of tumor xenografts in vivo. In biochemical assays, 107_A07 competes with both HGF/SF and its truncated splice variant NK1 for MET binding, despite the location of the antibody epitope on a domain (Ig1) not reported to bind NK1 or HGF/SF. Overlay of the Fab-MET crystal structure with the InternalinB-MET crystal structure shows that the 107_A07 Fab comes into close proximity with the HGF/SF-binding SEMA domain when MET is in the “compact”, InternalinB-bound conformation, but not when MET is in the “open” conformation. These findings provide further support for the importance of the “compact” conformation of the MET extracellular domain, and the relevance of this conformation to HGF/SF binding and signaling

Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22

Interleukin-22 (IL-22) is a critical immune defence cytokine that maintains intestinal homeostasis and promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the adenomatous polyposis coli gene (Apc) are a major driver of familial colorectal cancers (CRCs). How IL-22 contributes to APC-mediated tumorigenesis is poorly understood. To investigate IL-22 signalling in wild-type (WT) and APC-mutant cells, we performed RNA sequencing (RNAseq) of IL-22-treated murine small intestinal epithelial organoids. In WT epithelia, antimicrobial defence and cellular stress response pathways were most strongly induced by IL-22. Surprisingly, although IL-22 activates signal transducer and activator of transcription 3 (STAT3) in APC-mutant cells, STAT3 target genes were not induced. Our analyses revealed that ApcMin/Min cells are resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, particularly histone deacetylases (HDACs). We further show that IL-22 increases DNA damage and genomic instability, which can accelerate cellular transition from heterozygosity (ApcMin/+) to homozygosity (ApcMin/Min) to drive tumour formation. Our data reveal an unexpected role for IL-22 in promoting early tumorigenesis while excluding a function for IL-22 in transformed epithelial cells

Co-Conserved Features Associated with cis Regulation of ErbB Tyrosine Kinases

BACKGROUND: The epidermal growth factor receptor kinases, or ErbB kinases, belong to a large sub-group of receptor tyrosine kinases (RTKs), which share a conserved catalytic core. The catalytic core of ErbB kinases have functionally diverged from other RTKs in that they are activated by a unique allosteric mechanism that involves specific interactions between the kinase core and the flanking Juxtamembrane (JM) and COOH-terminal tail (C-terminal tail). Although extensive studies on ErbB and related tyrosine kinases have provided important insights into the structural basis for ErbB kinase functional divergence, the sequence features that contribute to the unique regulation of ErbB kinases have not been systematically explored. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we use a Bayesian approach to identify the selective sequence constraints that most distinguish ErbB kinases from other receptor tyrosine kinases. We find that strong ErbB kinase-specific constraints are imposed on residues that tether the JM and C-terminal tail to key functional regions of the kinase core. A conserved RIxKExE motif in the JM-kinase linker region and a glutamine in the inter-lobe linker are identified as two of the most distinguishing features of the ErbB family. While the RIxKExE motif tethers the C-terminal tail to the N-lobe of the kinase domain, the glutamine tethers the C-terminal tail to hinge regions critical for inter-lobe movement. Comparison of the active and inactive crystal structures of ErbB kinases indicates that the identified residues are conformationally malleable and can potentially contribute to the cis regulation of the kinase core by the JM and C-terminal tail. ErbB3, and EGFR orthologs in sponges and parasitic worms, diverge from some of the canonical ErbB features, providing insights into sub-family and lineage-specific functional specialization. CONCLUSION/SIGNIFICANCE: Our analysis pinpoints key residues for mutational analysis, and provides new clues to cancer mutations that alter the canonical modes of ErbB kinase regulation