Although epidermal growth factor receptor (EGFR)-targeted therapies are approved for colorectal cancer (CRC) treatment, only 15% of CRC patients respond to EGFR inhibition. Here, we show that colorectal cancers (CRC) can initiate and grow faster through an EGFR-independent mechanism, irrespective of the presence of EGFR, in two different mouse models using tissue-specific ablation of Egfr. The growth benefit in the absence of EGFR is also independent of Kras status. An EGFR-independent gene expression signature, also observed in human CRCs, revealed that anergy-inducing genes are overexpressed in EGFR-independent polyps, suggesting increased infiltration of anergic lymphocytes promotes an accelerated growth rate that is partially caused by escape from cell-mediated immune responses. Many genes in the EGFR-independent gene expression signature are downstream targets of interleukin 10 receptor alpha (IL10RA). We further show that IL10 is detectable in serum from mice with EGFR-independent colon polyps. Using organoids in vitro and Src ablation in vivo, we show that IL10 contributes to growth of EGFR-independent CRCs, potentially mediated by the well-documented role of SRC in IL10 signaling. Based on these data, we show that the combination of an EGFR inhibitor with an anti-IL10 neutralizing antibody results in decreased cell proliferation in organoids and in decreased polyp size in pre-clinical models harboring EGFR-independent CRCs, providing a new therapeutic intervention for CRCs resistant to EGFR inhibitor therapies.
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The datasets supporting the conclusions of this article are available within the article, its supplemental files, and from the corresponding author upon request. The high-throughput sequencing data are deposited in GEO.
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This work was supported by fellowships F31 AT002835 (ESR), F32 CA168301 (RML), T32 OD011083 (AP), and by NIH grants R01 CA092479 (DWT), NIEHS P30 ES029067, and the Tom and Jean McMullin Chair of Genetics (DWT). We thank members of the Threadgill lab for constructive criticism on manuscript drafts; Dr. Andrew Hillhouse and the Texas A&M Institute for Genome Sciences and Society’s (TIGSS) Molecular Genomics Core for RNAseq data generation; and Kristen Hanneman for mouse husbandry. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov.
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Mantilla-Rojas, C., Yu, M., Rinella, E.S. et al. A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy. Oncogene 40, 3047–3059 (2021). https://doi.org/10.1038/s41388-021-01752-2