sepantronium and Colorectal-Neoplasms

Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 157 CRC cell lines to CMS. By integrating results from large-scale drug screens, we discovered that the CMS1 subtype is highly vulnerable to the BIRC5 suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrated a 100-fold higher sensitivity of CMS1. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 CRC, low concentrations of YM155 induced apoptosis and expression signatures associated with ER stress-mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we further discovered a novel role of genes involved in LDL-receptor trafficking as modulators of YM155 sensitivity in the CRC cell line HCT116. Our work shows that combining drug response data with CMS classification in cell lines can reveal selective vulnerabilities and proposes YM155 as a novel subtype-specific drug.

Topics: Antineoplastic Agents; Apoptosis; Caco-2 Cells; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genome-Wide Association Study; HCT116 Cells; Humans; Imidazoles; Naphthoquinones; Polymorphism, Single Nucleotide; RNA Interference; Transcriptome

Colorectal cancer is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature, and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups have been limited.

Topics: Aged; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; bcl-X Protein; Cell Line, Tumor; Colorectal Neoplasms; Female; Humans; Imidazoles; Mice; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Naphthoquinones; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Sulfonamides; Xenograft Model Antitumor Assays

Photodynamic therapy (PDT) represents a rapidly developing alternative treatment for various types of cancers. Although considered highly effective, cancer cells can exploit various mechanisms, including the upregulation of apoptosis inhibitors, to overcome the cytotoxic effect of PDT. Survivin, a member of the inhibitor of apoptosis protein family, is known to play a critical role in cancer progression and therapeutic resistance and therefore represents a potential therapeutic target. The aim of this study was to investigate whether YM155, a small molecule inhibitor of survivin expression, can potentiate the cytotoxic effect of hypericin-mediated PDT (HY-PDT). Accordingly, two cell lines resistant to HY-PDT, HT-29 (colorectal adenocarcinoma) and A549 (lung adenocarcinoma), were treated either with HY-PDT alone or in combination with YM155. The efficacy of different treatment regimens was assessed by MTT assay, flow cytometry analysis of metabolic activity, viability, phosphatidylserine externalisation, mitochondrial membrane potential and caspase-3 activity and immunoblotting for the cleavage of poly (ADP-ribose) polymerase (PARP). Here we show for the first time that the repression of survivin expression by YM155 is effective in sensitizing HT-29 and A549 cells to HY-PDT, as measured by the decrease in cell viability and induction of apoptosis. Combined treatment with hypericin and YM155 led to a more severe dissipation of the mitochondrial membrane potential and caused an increase in caspase-3 activation and subsequent PARP cleavage. Our results demonstrate that the repression of survivin expression by YM155 potentially represents a novel alternative strategy to increase the efficacy of HY-PDT in cancer cells that are otherwise weakly responsive or non-responsive to treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anthracenes; Antineoplastic Agents; Autophagy; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Drug Resistance, Neoplasm; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Membrane Potential, Mitochondrial; Naphthoquinones; Perylene; Photochemotherapy; Photosensitizing Agents; Survivin