Reference - Detail
| RRC ID | 86126 |
|---|---|
| Author | Kilroy-Gehret MK, Wischmeier C, Park S, Choi D, Feroz W, Mishra R, Garrett JT. |
| Title | Co-targeting KRASG12D and the HER family is efficacious in colorectal cancer. |
| Journal | Carcinogenesis |
| Abstract |
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, with roughly 41% of CRC cases harboring a KRAS mutation. Acquired resistance to KRAS-targeted treatments has occurred with mechanisms including increased HER family expression among other receptor tyrosine kinases. HER3, a member of the HER family that is kinase impaired, has been shown to be a resistance mechanism upon inhibition of the HER family and downstream targets, including RAS/MEK/ERK and PI3K/AKT. We find that KRAS mutations tend to co-occur with HER3 alterations in a large panel of cancers and in CRCs. Our results show that both total and activated HER3 levels increase in CRC patient-derived organoids and cell lines after treatment with KRASG12D targeted agents, indicating that HER3 could be a potential adaptive response mechanism to KRAS-targeted therapy. Further, we found that genetic knock-down of KRAS and HER3 resulted in a reduction in the growth of CRC cells compared to a single knockdown of either KRAS or HER3. We observed that kinase-impaired HER3 binding partners, as assessed by immunoprecipitation, is cell dependent with EGFR binding HER3 in one cell line. After co-treating CRC cells with pan-HER inhibitors in combination with MRTX1133, a KRASG12D inhibitor, synergistic and additive effects in the reduction in cell growth were observed. Finally, we found that co-targeting KRASG12D mutant cells with a KRASG12D inhibitor and a HER3 antibody-drug conjugate further reduced cell viability. We posit that co-targeting both KRASG12D and HER3, whether directly or indirectly, is a potential therapeutic strategy in CRC patients. |
| Volume | 46(2) |
| Published | 2025-4-3 |
| DOI | 10.1093/carcin/bgaf036 |
| PII | 8221641 |
| PMID | 40755231 |
| MeSH | Cell Line, Tumor Cell Proliferation / drug effects Colorectal Neoplasms* / drug therapy Colorectal Neoplasms* / genetics Colorectal Neoplasms* / pathology Drug Resistance, Neoplasm / genetics ErbB Receptors / antagonists & inhibitors ErbB Receptors / genetics ErbB Receptors / metabolism Humans Mutation Organoids / drug effects Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins p21(ras)* / antagonists & inhibitors Proto-Oncogene Proteins p21(ras)* / genetics Proto-Oncogene Proteins p21(ras)* / metabolism Receptor, ErbB-3* / antagonists & inhibitors Receptor, ErbB-3* / genetics Receptor, ErbB-3* / metabolism |
| IF | 4.603 |
| Altmetric score |
オルトメトリクス指標項目
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| Total number of mentions | 0 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | CW-2(RCB0778) |