bims-pimaco 2023-12-24 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–12–24
seven papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

NUAK1 coordinates growth factor-dependent activation of mTORC2 and Akt signaling.
VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes.
Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies.
Amino acid availability governs mTOR ubiquitination.
Phase I study of mTORC1/2 inhibitor sapanisertib in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies.
Spatial pharmacology using mass spectrometry imaging.
SLC16a6, mTORC1, and Autophagy Regulate Ketone Body Excretion in the Intestinal Cells.

Cell Biosci. 2023 Dec 22. 13(1): 232

NUAK1 coordinates growth factor-dependent activation of mTORC2 and Akt signaling.

Mario Palma, Elizabeth Riffo, Alejandro Farias, Viviana Coliboro-Dannich, Luis Espinoza-Francine, Emilia Escalona, Roberto Amigo, José L Gutiérrez, Roxana Pincheira, Ariel F Castro.

   BACKGROUND: mTORC2 is a critical regulator of cytoskeleton organization, cell proliferation, and cancer cell survival. Activated mTORC2 induces maximal activation of Akt by phosphorylation of Ser-473, but regulation of Akt activity and signaling crosstalk upon growth factor stimulation are still unclear.
RESULTS: We identified that NUAK1 regulates growth factor-dependent activation of Akt by two mechanisms. NUAK1 interacts with mTORC2 components and regulates mTORC2-dependent activation of Akt by controlling lysosome positioning and mTOR association with this organelle. A second mechanism involves NUAK1 directly phosphorylating Akt at Ser-473. The effect of NUAK1 correlated with a growth factor-dependent activation of specific Akt substrates. NUAK1 induced the Akt-dependent phosphorylation of FOXO1/3a (Thr-24/Thr-32) but not of TSC2 (Thr-1462). According to a subcellular compartmentalization that could explain NUAK1's differential effect on the Akt substrates, we found that NUAK1 is associated with early endosomes but not with plasma membrane, late endosomes, or lysosomes. NUAK1 was required for the Akt/FOXO1/3a axis, regulating p21CIP1, p27KIP1, and FoxM1 expression and cancer cell survival upon EGFR stimulation. Pharmacological inhibition of NUAK1 potentiated the cell death effect induced by Akt or mTOR pharmacological blockage. Analysis of human tissue data revealed that NUAK1 expression positively correlates with EGFR expression and Akt Ser-473 phosphorylation in several human cancers.
CONCLUSIONS: Our results showed that NUAK1 kinase controls mTOR subcellular localization and induces Akt phosphorylation, demonstrating that NUAK1 regulates the growth factor-dependent activation of Akt signaling. Therefore, targeting NUAK1, or co-targeting it with Akt or mTOR inhibitors, may be effective in cancers with hyperactivated Akt signaling.

Keywords:  Akt; Cancer signaling; Co-targeting; NUAK1; mTORC2

DOI:  https://doi.org/10.1186/s13578-023-01185-2
Nat Commun. 2023 Dec 20. 14(1): 8464

VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes.

Tianyu Zhao, Yuanyuan Guan, Chenchen Xu, Dong Wang, Jialiang Guan, Ying Liu.

The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial regulator of cell growth. It senses nutrient signals and adjusts cellular metabolism accordingly. Deregulation of mTORC1 has been associated with metabolic diseases, cancer, and aging. Amino acid signals are transduced to mTORC1 through sensor proteins and two protein complexes named GATOR1 and GATOR2. In this study, we identify VWCE (von Willebrand factor C and EGF domains) as a negative regulator of amino acid-dependent mTORC1 signaling. Knockdown of VWCE promotes mTORC1 activity even in the absence of amino acids. VWCE interacts with the KICSTOR complex to facilitate the recruitment of GATOR1 to the lysosomes. Bioinformatic analysis reveals that expression of VWCE is reduced in prostate cancer. More importantly, overexpression of VWCE inhibits the development of prostate cancer. Therefore, VWCE may serve as a potential therapeutic target for the treatment of prostate cancers.

DOI: https://doi.org/10.1038/s41467-023-44241-8
Drugs. 2023 Dec 18.

Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies.

Bennett A Caughey, John H Strickler.

Kirsten rat sarcoma virus (KRAS) is one of the most important and frequently mutated oncogenes in cancer and the mutational prevalence is especially high in many gastrointestinal malignancies, including colorectal cancer and pancreatic ductal adenocarcinoma. The KRAS protein is a small GTPase that functions as an "on/off" switch to activate downstream signaling, mainly through the mitogen-activated protein kinase pathway. KRAS was previously considered undruggable because of biochemical constraints; however, recent breakthroughs have enabled the development of small-molecule inhibitors of KRAS G12C. These drugs were initially approved in lung cancer and have now shown substantial clinical activity in KRAS G12C-mutated pancreatic ductal adenocarcinoma as well as colorectal cancer when combined with anti-EGFR monoclonal antibodies. Early data are encouraging for other gastrointestinal cancers as well and many other combination strategies are being investigated. Several new KRAS G12C inhibitors and novel inhibitors of other KRAS alterations have recently entered the clinic. These molecules employ a variety of innovative mechanisms and have generated intense interest. These novel drugs are especially important as KRAS G12C is rare in gastrointestinal malignancies compared with other KRAS alterations, representing potentially groundbreaking advances. Soon, the rapidly evolving landscape of novel KRAS inhibitors may substantially shift the therapeutic landscape for gastrointestinal cancers and offer meaningful survival improvements.

DOI: https://doi.org/10.1007/s40265-023-01980-8
Cell Res. 2023 Dec 15.

Amino acid availability governs mTOR ubiquitination.

Xiaoming Dai, Peiqiang Yan, Wenyi Wei.

DOI: https://doi.org/10.1038/s41422-023-00910-3
Cancer Res Commun. 2023 Dec 21.

Phase I study of mTORC1/2 inhibitor sapanisertib in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies.

Vivek Subbiah, Niamh Coleman, Sarina A Piha-Paul, Apostolia M Tsimberidou, Filip Janku, Jordi Rodon, Shubham Pant, Ecaterina E Dumbrava, Siqing Fu, David S Hong, Shizhen Zhang, Ming Sun, Yunfang Jiang, Jason Roszik, Juhee Song, Ying Yuan, Funda Meric-Bernstam, Aung Naing.

BACKGROUND: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. We report preliminary safety, and efficacy of sapanisertib in combination with metformin.
METHODS: Patients with advanced metastatic solid tumors refractory to standard treatment, with/without mTOR/AKT/PI3Kpathway alterations, received sapanisertib 3mg or 4mg daily together with metformin once to three times daily (500mg - 1500mg).
RESULTS: 30 pts were enrolled across 4 cohorts (3mg/500mg; 3mg/1000mg, 4mg/1000mg; 4mg/1500mg). 19 were female (63%), median age was 57 (range: 30-77). Tumor types included sarcoma (6), breast (4), ovarian (4) among others. Most common genomic alterations included PIK3CA (27%), PTEN(17%), AKT1/2 (10%), mTOR (10%). Of 30 pts evaluable for response, 4 pts achieved partial response (PR); 15 pts achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3/4pts had documented PTEN mutations (3/5 pts enrolled with PTEN mutations had PR); 2/4 of pts in PR had co-mutations (pt with leiomyosarcoma had both PTEN and TSC; pt with breast cancer had both PTEN and STK11); 1/4 pts in PR had AKT and mTOR mutation. Grade (G) 3-5 treatment-related adverse events included hyperglycemia (4/30; 13%) fatigue (2/30; 7%) hypertriglyceridemia (1/30; 3%) rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). 4mg/1000mg was defined as the maximum tolerated dose.
CONCLUSIONS: The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with anti-tumor activity observed in patients with advanced malignancies harboring PTEN/ AKT/mTOR pathway alterations.

DOI: https://doi.org/10.1158/2767-9764.CRC-22-0260
Trends Pharmacol Sci. 2023 Dec 15. pii: S0165-6147(23)00255-9. [Epub ahead of print]

Spatial pharmacology using mass spectrometry imaging.

Presha Rajbhandari, Taruna V Neelakantan, Noreen Hosny, Brent R Stockwell.

  The emerging and powerful field of spatial pharmacology can map the spatial distribution of drugs and their metabolites, as well as their effects on endogenous biomolecules including metabolites, lipids, proteins, peptides, and glycans, without the need for labeling. This is enabled by mass spectrometry imaging (MSI) that provides previously inaccessible information in diverse phases of drug discovery and development. We provide a perspective on how MSI technologies and computational tools can be implemented to reveal quantitative spatial drug pharmacokinetics and toxicology, tissue subtyping, and associated biomarkers. We also highlight the emerging potential of comprehensive spatial pharmacology through integration of multimodal MSI data with other spatial technologies. Finally, we describe how to overcome challenges including improving reproducibility and compound annotation to generate robust conclusions that will improve drug discovery and development processes.

Keywords:  DES; MALDI; SIMS; imaging; mass spectrometry imaging; multimodal imaging

DOI:  https://doi.org/10.1016/j.tips.2023.11.003
Biology (Basel). 2023 Nov 26. pii: 1467. [Epub ahead of print]12(12):

SLC16a6, mTORC1, and Autophagy Regulate Ketone Body Excretion in the Intestinal Cells.

Takashi Uebanso, Moeka Fukui, Chisato Naito, Takaaki Shimohata, Kazuaki Mawatari, Akira Takahashi.

  Ketone bodies serve several functions in the intestinal epithelium, such as stem cell maintenance, cell proliferation and differentiation, and cancer growth. Nevertheless, there is limited understanding of the mechanisms governing the regulation of intestinal ketone body concentration. In this study, we elucidated the factors responsible for ketone body production and excretion using shRNA-mediated or pharmacological inhibition of specific genes or functions in the intestinal cells. We revealed that a fasting-mimicked culture medium, which excluded glucose, pyruvate, and glutamine, augmented ketone body production and excretion in the Caco2 and HT29 colorectal cells. This effect was attenuated by glucose or glutamine supplementation. On the other hand, the inhibition of the mammalian target of rapamycin complex1 (mTORC1) recovered a fraction of the excreted ketone bodies. In addition, the pharmacological or shbeclin1-mediated inhibition of autophagy suppressed ketone body excretion. The knockdown of basigin, a transmembrane protein responsible for targeting monocarboxylate transporters (MCTs), such as MCT1 and MCT4, suppressed lactic acid and pyruvic acid excretion but increased ketone body excretion. Finally, we found that MCT7 (SLC16a6) knockdown suppressed ketone body excretion. Our findings indicate that the mTORC1-autophagy axis and MCT7 are potential targets to regulate ketone body excretion from the intestinal epithelium.

Keywords:  autophagy; intestinal cell; ketone body; mTORC1; solute carrier family 16 member 6: SLC16a6 (MCT7)

DOI:  https://doi.org/10.3390/biology12121467