Publications by authors named "Eranga R Balasooriya"

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition.

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Article Synopsis
  • FGFR2 and FGFR3 are proteins that can become cancer-causing (oncogenic) through changes, and they are important in certain types of cancers like bile duct cancer and bladder cancer.
  • A new drug called KIN-3248 was tested and showed it can still work against some common mutations that make other drugs ineffective.
  • KIN-3248 might be a promising treatment for these cancers, especially when used with other drugs that target different cancer pathways.
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Unlabelled: Beyond the most common oncogenes activated by mutation (mut-drivers), there likely exists a variety of low-frequency mut-drivers, each of which is a possible frontier for targeted therapy. To identify new and understudied mut-drivers, we developed a machine learning (ML) model that integrates curated clinical cancer data and posttranslational modification (PTM) proteomics databases. We applied the approach to 62,746 patient cancers spanning 84 cancer types and predicted 3,964 oncogenic mutations across 1,148 genes, many of which disrupt PTMs of known and unknown function.

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Purpose: FGFR inhibitors are effective in FGFR2-altered cholangiocarcinoma, leading to approval of reversible FGFR inhibitors, pemigatinib and infigratinib, and an irreversible inhibitor, futibatinib. However, acquired resistance develops, limiting clinical benefit. Some mechanisms of resistance have been reported, including secondary FGFR2 kinase domain mutations.

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  • PTOV1 is a cancer-related protein linked to prostate cancer that enhances cell growth and movement, but how it is regulated is still uncertain.
  • * Researchers found that the protein 14-3-3 interacts with PTOV1 and both proteins are associated with the worsening of prostate cancer when present at high levels.
  • * The study reveals that 14-3-3 stabilizes PTOV1 by preventing its degradation, suggesting a potential new target for cancer therapy.*
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TNK1 is a non-receptor tyrosine kinase with poorly understood biological function and regulation. Here, we identify TNK1 dependencies in primary human cancers. We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.

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ATG9A, the only multi-pass transmembrane protein among core ATG proteins, is an essential regulator of autophagy, yet its regulatory mechanisms and network of interactions are poorly understood. Through quantitative BioID proteomics, we identify a network of ATG9A interactions that includes members of the ULK1 complex and regulators of membrane fusion and vesicle trafficking, including the TRAPP, EARP, GARP, exocyst, AP-1, and AP-4 complexes. These interactions mark pathways of ATG9A trafficking through ER, Golgi, and endosomal systems.

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