2. Academic Validation
  3. Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization

Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization

  • NPJ Precis Oncol. 2025 Jan 6;9(1):4. doi: 10.1038/s41698-024-00793-6.
Kohei Maruyama 1 2,  Yuki Shimizu 1,  Yumi Nomura 3 4,  Tomoko Oh-Hara 1,  Yuki Takahashi 3 4,  Satoshi Nagayama 5 6 7,  Naoya Fujita 8,  Ryohei Katayama 9 10
Affiliations

Affiliations

  • 1 Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
  • 3 Business Development Division, Technical Research Institute, TOPPAN Holdings Inc., Saitama, Japan.
  • 4 Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 5 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 6 Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 7 Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, Japan.
  • 8 Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 9 Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. ryohei.katayama@jfcr.or.jp.
  • 10 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. ryohei.katayama@jfcr.or.jp.
PMID: 39762482 DOI: 10.1038/s41698-024-00793-6
Abstract

KRAS-specific inhibitors have shown promising antitumor effects, especially in non-small cell lung Cancer, but limited efficacy in colorectal Cancer (CRC) patients. Recent studies have shown that EGFR-mediated adaptive feedback mediates primary resistance to KRAS inhibitors, but the Other resistance mechanisms have not been identified. In this study, we investigated intrinsic resistance mechanisms to KRAS inhibitors using patient-derived CRC cells (CRC-PDCs). We found that KRAS-mutated CRC-PDCs can be divided into at least an EGFR pathway-activated group and a PI3K/Akt pathway-activated group. In the latter group, PDCs with PIK3CA major mutation showed high sensitivity to PI3K+mTOR co-inhibition, and a PDC with Her2 amplification with PIK3CA minor mutation showed PI3K-AKT pathway dependency but lost KRAS-MAPK dependency by cytoplasmic localization of KRAS. In the PDC, Her2 knockout restored KRAS plasma membrane localization and KRAS inhibitor sensitivity. The current study provides insight into the mechanisms of primary resistance to KRAS inhibitors, including aberrant KRAS localization.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    99.94%, KRAS G12C Inhibitor
    Ras