bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2024–03–10
seven papers selected by
Lucas B. Zeiger
  1. mTORC2-AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells.
  2. Growth Signaling Networks Orchestrate Cancer Metabolic Networks.
  3. Twelve-month progression-free survival with sotorasib and panitumumab in KRAS G12C mutant metastatic colorectal cancer.
  4. Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D.
  5. Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex.
  6. Drug-drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers.
  7. Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
  1. FASEB J. 2024 Mar 15. 38(5): e23532
    mTORC2-AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells.
    Mengzhen Li, Xi Wu, Yuwei Pan, Manyu Song, Xu Yang, Jiuzhi Xu, Maksim V Plikus, Cong Lv, Lu Yu, Zhengquan Yu.
      Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem cells and cancer, its regulatory mechanisms are still being updated. Here, we found a previously unappreciated mechanism of mammalian target of rapamycin complex 2 (mTORC2) in regulating glycolysis in intestinal stem cell maintenance and cancer progression. mTORC2 key subunits expression levels and its kinase activity were specifically upregulated in intestinal stem cells, mouse intestinal tumors, and human colorectal cancer (CRC) tissues. Genetic ablation of its key scaffolding protein Rictor in both mouse models and cell lines revealed that mTORC2 played an important role in promoting intestinal stem cell proliferation and self-renewal. Moreover, utilizing mouse models and organoid culture, mTORC2 loss of function was shown to impair growth of gut adenoma and tumor organoids. Based on these findings, we performed RNA-seq and noticed significant metabolic reprogramming in Rictor conditional knockout mice. Among all the pathways, carbohydrate metabolism was most profoundly altered, and further studies demonstrated that mTORC2 promoted glycolysis in intestinal epithelial cells. Most importantly, we showed that a rate-limiting enzyme in regulating glycolysis, 6-phosphofructo-2-kinase (PFKFB2), was a direct target for the mTORC2-AKT signaling. PFKFB2 was phosphorylated upon mTORC2 activation, but not mTORC1, and this process was AKT-dependent. Together, this study has identified a novel mechanism underlying mTORC2 activated glycolysis, offering potential therapeutic targets for treating CRC.
    Keywords:  PFKFB2; glycolysis; intestinal stem cells; mTORC2; tumorigenesis
    DOI:  https://doi.org/10.1096/fj.202301833RR
  2. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041543. [Epub ahead of print]
    Growth Signaling Networks Orchestrate Cancer Metabolic Networks.
    Brendan D Manning, Christian C Dibble.
      Normal cells grow and divide only when instructed to by signaling pathways stimulated by exogenous growth factors. A nearly ubiquitous feature of cancer cells is their capacity to grow independent of such signals, in an uncontrolled, cell-intrinsic manner. This property arises due to the frequent oncogenic activation of core growth factor signaling pathway components, including receptor tyrosine kinases, PI3K-AKT, RAS-RAF, mTORC1, and MYC, leading to the aberrant propagation of pro-growth signals independent of exogenous growth factors. The growth of both normal and cancer cells requires the acquisition of nutrients and their anabolic conversion to the primary macromolecules underlying biomass production (protein, nucleic acids, and lipids). The core growth factor signaling pathways exert tight regulation of these metabolic processes and the oncogenic activation of these pathways drive the key metabolic properties of cancer cells and tumors. Here, we review the molecular mechanisms through which these growth signaling pathways control and coordinate cancer metabolism.
    DOI:  https://doi.org/10.1101/cshperspect.a041543
  3. Anticancer Drugs. 2024 Mar 05.
    Twelve-month progression-free survival with sotorasib and panitumumab in KRAS G12C mutant metastatic colorectal cancer.
    Gozde Kavgaci, Omer Dizdar, Suayib Yalcin.
      Colorectal cancer (CRC) ranks third in global cancer prevalence, with 40% presenting as metastatic colorectal cancer (mCRC). KRAS mutations in mCRC patients confer resistance to anti-EGFR treatments. Promising inhibitors such as sotorasib and adagrasib targeting KRASG12C mutations have demonstrated efficacy. Herein, we present a heavily pretreated mCRC case with a progression-free survival of 12 months with sotorasib and panitumumab. In 2017, a 27-year-old male presented with abdominal pain and received a diagnosis of stage IIIC KRAS G12C mutant CRC. Following surgery and adjuvant chemotherapy, he developed metastases in the liver and lungs in 2020. Treatment with FOLFIRINOX and bevacizumab, and later FOLFIRI and bevacizumab, with surgeries and local interventions resulted in partial responses. Upon disease progression, sotorasib and panitumumab were initiated, achieving a complete metabolic response. After 12 months of progression-free survival, oligoprogressive liver lesions were surgically resected. This case highlights the remarkable outcome of a heavily treated KRAS G12C mutant mCRC patient. The combination of sotorasib and panitumumab, along with multidisciplinary approaches including surgery and local interventions, played an important role in our patient's survival.
    DOI:  https://doi.org/10.1097/CAD.0000000000001587
  4. Nat Chem Biol. 2024 Mar 05.
    Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D.
    Qinheng Zheng, Ziyang Zhang, Keelan Z Guiley, Kevan M Shokat.
      K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven cancer cell proliferation in vitro and xenograft growth in mice.
    DOI:  https://doi.org/10.1038/s41589-024-01565-w
  5. Life Sci Alliance. 2024 May;pii: e202302245. [Epub ahead of print]7(5):
    Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex.
    Andreas Damianou, Zhu Liang, Frederik Lassen, Iolanda Vendrell, George Vere, Svenja Hester, Philip D Charles, Adan Pinto-Fernandez, Alberto Santos, Roman Fischer, Benedikt M Kessler.
      KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute to ∼30% of human solid tumours, including lung adenocarcinoma, pancreatic, and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. However, the precise signalling cascades these mutations affect are poorly understood. Here, APEX2 proximity labelling was used to profile the molecular environment of WT, G12D, G13D, and Q61H-activating KRAS mutants under starvation and stimulation conditions. Through quantitative proteomics, we demonstrate the presence of known KRAS interactors, including ARAF and LZTR1, which are differentially captured by WT and KRAS mutants. Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.
    DOI:  https://doi.org/10.26508/lsa.202302245
  6. Bioorg Med Chem. 2024 Mar 02. pii: S0968-0896(24)00088-9. [Epub ahead of print]102 117674
    Drug-drug conjugates of MEK and Akt inhibitors for RAS-mutant cancers.
    Hikaru Fujita, Sachiko Arai, Hiroshi Arakawa, Kana Hamamoto, Toshiyuki Kato, Tsubasa Arai, Nanaka Nitta, Kazuki Hotta, Natsuko Hosokawa, Takako Ohbayashi, Chiaki Takahashi, Yasuhide Inokuma, Ikumi Tamai, Seiji Yano, Munetaka Kunishima, Yoshihiro Watanabe.
      Controlling RAS mutant cancer progression remains a significant challenge in developing anticancer drugs. Whereas Ras G12C-covalent binders have received clinical approval, the emergence of further mutations, along with the activation of Ras-related proteins and signals, has led to resistance to Ras binders. To discover novel compounds to overcome this bottleneck, we focused on the concurrent and sustained blocking of two major signaling pathways downstream of Ras. To this end, we synthesized 25 drug-drug conjugates (DDCs) by combining the MEK inhibitor trametinib with Akt inhibitors using seven types of linkers with structural diversity. The DDCs were evaluated for their cell permeability/accumulation and ability to inhibit proliferation in RAS-mutant cell lines. A representative DDC was further evaluated for its effects on signaling proteins, induction of apoptosis-related proteins, and the stability of hepatic metabolic enzymes. These in vitro studies identified a series of DDCs, especially those containing a furan-based linker, with promising properties as agents for treating RAS-mutant cancers. Additionally, in vivo experiments in mice using the two selected DDCs revealed prolonged half-lives and anticancer efficacies comparable to those of trametinib. The PK profiles of trametinib and the Akt inhibitor were unified through the DDC formation. The DDCs developed in this study have potential as drug candidates for the broad inhibition of RAS-mutant cancers.
    Keywords:  Akt inhibitor; Downstream signal; Linker; RAS-mutations; Trametinib; drug–drug conjugate (DDC)
    DOI:  https://doi.org/10.1016/j.bmc.2024.117674
  7. Nat Commun. 2024 Mar 02. 15(1): 1931
    Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
    Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.
      Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46114-0
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