bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2024‒06‒09
six papers selected by
Lucas B. Zeiger
  1. APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.
  2. KRAS G12C Inhibitors in the Treatment of Metastatic Colorectal Cancer.
  3. TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.
  4. Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.
  5. 4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.
  6. Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells.
  1. Aging (Albany NY). 2024 Jun 06. 16
    APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.
    Yu-Lin Liu, Zhuo Xiang, Bo-Ya Zhang, Yu-Wei Zou, Gui-Lai Chen, Li Yin, Yan-Long Shi, Li-Li Xu, Jingwang Bi, Qiang Wang.
      Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.
    Keywords:  PIK3CA mutation; apolipoprotein A5; colorectal cancer; oxaliplatin resistance; reactive oxygen species
    DOI:  https://doi.org/10.18632/aging.205872
  2. Clin Colorectal Cancer. 2024 May 13. pii: S1533-0028(24)00034-3. [Epub ahead of print]
    KRAS G12C Inhibitors in the Treatment of Metastatic Colorectal Cancer.
    Annie Xiao, Marwan Fakih.
      KRAS mutations contribute substantially to the overall colorectal cancer burden and have long been a focus of drug development efforts. After a lengthy preclinical road, KRAS inhibition via the G12C allele has finally become a therapeutic reality. Unlike in NSCLC, early studies of KRAS inhibitors in CRC struggled to demonstrate single agent activity. Investigation into these tissue-specific treatment differences has led to a deeper understanding of the complexities of MAPK signaling and the diverse adaptive feedback responses to KRAS inhibition. EGFR reactivation has emerged as a principal resistance mechanism to KRAS inhibitor monotherapy. Thus, the field has pivoted to dual EGFR/KRAS blockade with promising efficacy. Despite significant strides in the treatment of KRAS G12C mutated CRC, new challenges are on the horizon. Alternative RTK reactivation and countless acquired molecular resistance mechanisms have shifted the treatment goalpost. This review focuses on the historical and contemporary clinical strategies of targeting KRAS G12C alterations in CRC and highlights future directions to overcome treatment challenges.
    Keywords:  Combination therapies; KRAS G12C inhibitor resistance mechanisms; RAS inhibitors; Targeted therapy
    DOI:  https://doi.org/10.1016/j.clcc.2024.05.004
  3. Cell Biosci. 2024 Jun 01. 14(1): 68
    TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.
    Canrong Li, Yuguo Yi, Yingyi Ouyang, Fengzhi Chen, Chuxin Lu, Shujun Peng, Yifan Wang, Xinyu Chen, Xiao Yan, Haolun Xu, Shuiming Li, Lin Feng, Xiaoduo Xie.
      BACKGROUND: Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is an effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration. However, an efficient tool for monitoring mTORC1 inhibition in living cells or tissues is lacking.RESULTS: We developed a genetically encoded mTORC1 sensor called TORSEL. This sensor changes its fluorescence pattern from diffuse to punctate when 4EBP1 dephosphorylation occurs and interacts with eIF4E. TORSEL can specifically sense the physiological, pharmacological, and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, TORSEL is a valuable tool for imaging-based visual screening of mTORC1 inhibitors. Using TORSEL, we identified histone deacetylase inhibitors that selectively block nutrient-sensing signaling to inhibit mTORC1.
    CONCLUSIONS: TORSEL is a unique living cell sensor that efficiently detects the inhibition of mTORC1 activity, and histone deacetylase inhibitors such as panobinostat target mTORC1 signaling through amino acid sensing.
    Keywords:  Amino acid sensing; HDAC inhibitor; Live-cell sensor; Panobinostat; mTORC1
    DOI:  https://doi.org/10.1186/s13578-024-01250-4
  4. Science. 2024 Jun 07. 384(6700): eadk0775
    Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.
    Jeffrey A Klomp, Jennifer E Klomp, Clint A Stalnecker, Kirsten L Bryant, A Cole Edwards, Kristina Drizyte-Miller, Priya S Hibshman, J Nathaniel Diehl, Ye S Lee, Alexis J Morales, Khalilah E Taylor, Sen Peng, Nhan L Tran, Laura E Herring, Alex W Prevatte, Natalie K Barker, Laura D Hover, Jill Hallin, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M Goodwin, Prson Gautam, Peter Olson, James G Christensen, John P Shen, Scott Kopetz, Lee M Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D Cox, Channing J Der.
      How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.
    DOI:  https://doi.org/10.1126/science.adk0775
  5. JCI Insight. 2024 Jun 06. pii: e177857. [Epub ahead of print]
    4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.
    Jiaxin Yin, Jianfeng Chen, Jing Han Hong, Yulin Huang, Rong Xiao, Shini Liu, Peng Deng, Yichen Sun, Kelila Xin Ye Chai, Xian Zeng, Jason Yongsheng Chan, Peiyong Guan, Yali Wang, Peili Wang, Chongjie Tong, Qiang Yu, Xiaojun Xia, Choon Kiat Ong, Bin Tean Teh, Ying Xiong, Jing Tan.
      Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here we show that ferroptosis negative regulation (FNR) signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/4EBP1 signaling promoted SLC7A11 protein synthesis, leading to ferroptosis inhibition in MEK inhibitor resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR-4EBP1 activity to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.
    Keywords:  Cancer; Drug therapy; Oncology; Therapeutics; Translation
    DOI:  https://doi.org/10.1172/jci.insight.177857
  6. Cell. 2024 Jun 06. pii: S0092-8674(24)00491-4. [Epub ahead of print]187(12): 3039-3055.e14
    Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells.
    Claudia Capdevila, Jonathan Miller, Liang Cheng, Adam Kornberg, Joel J George, Hyeonjeong Lee, Theo Botella, Christine S Moon, John W Murray, Stephanie Lam, Ruben I Calderon, Ermanno Malagola, Gary Whelan, Chyuan-Sheng Lin, Arnold Han, Timothy C Wang, Peter A Sims, Kelley S Yan.
      In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreERT2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.
    Keywords:  Fgfbp1; Lgr5; crypt base columnar cells; intestinal epithelium; intestinal stem cells; intestinal upper crypt; lineage hierarchy; time-resolved fate mapping; tissue regeneration; transit-amplifying cells
    DOI:  https://doi.org/10.1016/j.cell.2024.05.001
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