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Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening. | LitMetric

AI Article Synopsis

  • Colorectal cancer (CRC) organoids can be created from almost any CRC patient, reflecting the genetic variety of the disease, and a panel was developed that includes organoids with both normal and mutant RAS genes.
  • Research showed that organoids with mutant RAS are resistant to targeted therapies being tested in clinical trials, impacting both tumor and normal organoids.
  • Combining treatments that inhibit the EGFR-MEK-ERK pathway resulted in a temporary halt in cell division in the mutant RAS organoids, rather than cell death, indicating important implications for future drug evaluations using patient-derived organoid models.

Article Abstract

Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that are currently in clinical trial for RAS mutant cancers. Presence of mutant RAS correlated strongly with resistance to these targeted therapies. This was observed in tumorigenic as well as in normal organoids. Moreover, dual inhibition of the EGFR-MEK-ERK pathway in RAS mutant organoids induced a transient cell-cycle arrest rather than cell death. In vivo drug response of xenotransplanted RAS mutant organoids confirmed this growth arrest upon pan-HER/MEK combination therapy. Altogether, our studies demonstrate the potential of patient-derived CRC organoid libraries in evaluating inhibitors and drug combinations in a preclinical setting.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127645PMC
http://dx.doi.org/10.7554/eLife.18489DOI Listing

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