2. Academic Validation
  3. PDP1 promotes KRAS mutant colorectal cancer progression by serving as a scaffold for BRAF and MEK1

PDP1 promotes KRAS mutant colorectal cancer progression by serving as a scaffold for BRAF and MEK1

  • Cancer Lett. 2024 Jun 5:597:217007. doi: 10.1016/j.canlet.2024.217007.
Ming Yuan 1,  Chi Zhang 1,  Shaopeng Chen 1,  Shubiao Ye 1,  Huashan Liu 1,  Haoxian Ke 2,  Junfeng Huang 1,  Guanzhan Liang 1,  Runfeng Yu 1,  Tuo Hu 3,  Xianrui Wu 4,  Ping Lan 5
Affiliations

Affiliations

  • 1 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China.
  • 2 Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510288, PR China.
  • 3 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China. Electronic address: hutuo3@mail.sysu.edu.cn.
  • 4 Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510288, PR China. Electronic address: wuxianr5@mail.sysu.edu.cn.
  • 5 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China; State Key Laboratory of Oncology in South China, PR China. Electronic address: lanping@mail.sysu.edu.cn.
PMID: 38849010 DOI: 10.1016/j.canlet.2024.217007
Abstract

The oncogenic role of KRAS in colorectal Cancer (CRC) progression is well-established. Despite this, identifying effective therapeutic targets for KRAS-mutated CRC remains a significant challenge. This study identifies pyruvate dehydrogenase Phosphatase catalytic subunit 1 (PDP1) as a previously unrecognized yet crucial regulator in the progression of KRAS mutant CRC. A substantial upregulation of PDP1 expression is observed in KRAS mutant CRC cells and tissues compared to wild-type KRAS samples, which correlates with poorer prognosis. Functional experiments elucidate that PDP1 accelerates the malignance of KRAS mutant CRC cells, both in vitro and in vivo. Mechanistically, PDP1 acts as a scaffold, enhancing BRaf and MEK1 interaction and activating the MAPK signaling, thereby promoting CRC progression. Additionally, transcription factor KLF5 is identified as the key regulator for PDP1 upregulation in KRAS mutant CRC. Crucially, targeting PDP1 combined with MAPK inhibitors exhibits an obvious inhibitory effect on KRAS mutant CRC. Overall, PDP1 is underscored as a vital oncogenic driver and promising therapeutic target for KRAS mutant CRC.

Keywords

Colorectal cancer; Mutant KRAS; PDP1; Scaffold; Sotorasib.

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