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CANCER THERAPY

Bispecific antibodies seek out colon cancer stem cells

Nature Cancer volume 3, pages 379–380 (2022)Cite this article

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Patients with KRAS-mutant colorectal cancers do not respond to cetuximab, a monoclonal antibody against EGFR. A new proof-of-concept study presents a bispecific antibody with the ability to trigger EGFR degradation in LGR5+ cancer stem cells, and robust anti-tumor activity in KRAS-mutant and wild-type colorectal cancers.

Analogous to dedicated populations of adult stem cells in normal tissues, many cancers are also sustained by cancer stem cells (CSCs)1. The membrane protein LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5) is a marker of colon stem cells, as well as CSC subsets in human colorectal cancers (CRCs)1. However, efforts to therapeutically target LGR5-positive (LRG5+) CSCs fail to eradicate tumors, in part due to plasticity within the tumor through which LGR5-negative (LGR5–) cells can repopulate the pool of LGR5+ CSCs once treatment has desisted2,3. Another confounding factor for the clinical application of LGR5-directed therapy is that LGR5 is not only expressed by stem cells of the intestine but also in other tissues, such as the liver4, so eliminating LGR5+ cells may disrupt tissue integrity in many organ systems and lead to untoward side effects.

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Fig. 1: A bispecific antibody that specifically triggers EGFR degradation in LGR5+ colorectal CSCs.

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Authors and Affiliations

  1. Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA

    Norihiro Goto & Ömer H. Yilmaz

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ömer H. Yilmaz

  3. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Ömer H. Yilmaz

Authors
  1. Norihiro Goto
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  2. Ömer H. Yilmaz
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Correspondence to Ömer H. Yilmaz.

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Competing interests

O.H.Y. is a member of the scientific advisory board of AVA Therapeutics.

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Goto, N., Yilmaz, Ö.H. Bispecific antibodies seek out colon cancer stem cells. Nat Cancer 3, 379–380 (2022). https://doi.org/10.1038/s43018-022-00368-z

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