bims-pimaco 2023-05-07 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–05–07
nine papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

CD40 induces selective routing of Ras isoforms to subcellular compartments.
Targeting the biology of aging with mTOR inhibitors.
An integrated model for predicting KRAS dependency.
Targeting Myc-driven stress addiction in colorectal cancer.
mTORC2 interactome and localization determine aggressiveness of high-grade glioma cells through association with gelsolin.
Inorganic pyrophosphatase 1 activates the phosphatidylinositol 3-kinase/Akt signaling to promote tumorigenicity and stemness properties in colorectal cancer.
The Patent Landscape of mTOR and PTEN Targets.
Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer.
The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase.

J Cell Commun Signal. 2023 May 01.

CD40 induces selective routing of Ras isoforms to subcellular compartments.

Arathi Nair, Sushmita Chakraborty, Bhaskar Saha.

  Ras GTPases are central to cellular signaling and oncogenesis. The three loci of the Ras gene encode for four protein isoforms namely Harvey-Ras (H-Ras), Kirsten-Ras (K-Ras 4A and 4B), and Neuroblastoma-Ras (N-Ras) which share ~ 80% sequence similarity and used to be considered functionally redundant. The small molecule inhibitors of Ras lack specificity for the isoforms leading to widespread toxicity in Ras-targeted therapeutics. Ras isoforms' tissue-specific expression and selective association with carcinogenesis, embryonic development, and infection suggested their non-redundancy. We show that CD40, an antigen-presenting cell (APC)-expressed immune receptor, induces selective relocation of H-Ras, K-Ras, and N-Ras to the Plasma membrane (PM) lipid rafts, mitochondria, endoplasmic reticulum (ER), but not to the Golgi complex (GC). The two palmitoylated Ras isoforms-H-Ras and N-Ras-have a similar pattern of colocalization into the lipid-rich raft microdomain of the PM at early time points when compared to non-palmitoylated K-Ras (4B) with polylysine residues. CD40-induced trafficking of H-Ras and K-Ras to mitochondria and ER was found to be similar but different from that of N-Ras. Trafficking of all the Ras isoforms to the GC was independent of CD40 stimulation. The receptor-driven trafficking and spatial segregation of H-Ras, K-Ras, and N-Ras imply isoform-specific subcellular signaling platforms for the functional non-redundancy of Ras isoforms. PDB structures have been modified to illustrate various signaling proteins.

Keywords:  Endoplasmic reticulum; Golgi complex; Mitochondria; Ras-isoforms; Specificity

DOI:  https://doi.org/10.1007/s12079-023-00747-w
Nat Aging. 2023 May 04.

Targeting the biology of aging with mTOR inhibitors.

Joan B Mannick, Dudley W Lamming.

Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.

DOI: https://doi.org/10.1038/s43587-023-00416-y
PLoS Comput Biol. 2023 May 04. 19(5): e1011095

An integrated model for predicting KRAS dependency.

Yihsuan S Tsai, Yogitha S Chareddy, Brandon A Price, Joel S Parker, Chad V Pecot.

The clinical approvals of KRAS G12C inhibitors have been a revolutionary advance in precision oncology, but response rates are often modest. To improve patient selection, we developed an integrated model to predict KRAS dependency. By integrating molecular profiles of a large panel of cell lines from the DEMETER2 dataset, we built a binary classifier to predict a tumor's KRAS dependency. Monte Carlo cross validation via ElasticNet within the training set was used to compare model performance and to tune parameters α and λ. The final model was then applied to the validation set. We validated the model with genetic depletion assays and an external dataset of lung cancer cells treated with a G12C inhibitor. We then applied the model to several Cancer Genome Atlas (TCGA) datasets. The final "K20" model contains 20 features, including expression of 19 genes and KRAS mutation status. In the validation cohort, K20 had an AUC of 0.94 and accurately predicted KRAS dependency in both mutant and KRAS wild-type cell lines following genetic depletion. It was also highly predictive across an external dataset of lung cancer lines treated with KRAS G12C inhibition. When applied to TCGA datasets, specific subpopulations such as the invasive subtype in colorectal cancer and copy number high pancreatic adenocarcinoma were predicted to have higher KRAS dependency. The K20 model has simple yet robust predictive capabilities that may provide a useful tool to select patients with KRAS mutant tumors that are most likely to respond to direct KRAS inhibitors.

DOI: https://doi.org/10.1371/journal.pcbi.1011095
Drug Resist Updat. 2023 Apr 20. pii: S1368-7646(23)00046-8. [Epub ahead of print]69 100963

Targeting Myc-driven stress addiction in colorectal cancer.

Haris Saeed, Brian J Leibowitz, Lin Zhang, Jian Yu.

MYC is a proto-oncogene that encodes a powerful regulator of transcription and cellular programs essential for normal development, as well as the growth and survival of various types of cancer cells. MYC rearrangement and amplification is a common cause of hematologic malignancies. In epithelial cancers such as colorectal cancer, genetic alterations in MYC are rare. Activation of Wnt, ERK/MAPK, and PI3K/mTOR pathways dramatically increases Myc levels through enhanced transcription, translation, and protein stability. Elevated Myc promotes stress adaptation, metabolic reprogramming, and immune evasion to drive cancer development and therapeutic resistance through broad changes in transcriptional and translational landscapes. Despite intense interest and effort, Myc remains a difficult drug target. Deregulation of Myc and its targets has profound effects that vary depending on the type of cancer and the context. Here, we summarize recent advances in the mechanistic understanding of Myc-driven oncogenesis centered around mRNA translation and proteostress. Promising strategies and agents under development to target Myc are also discussed with a focus on colorectal cancer.

DOI: https://doi.org/10.1016/j.drup.2023.100963
Sci Rep. 2023 Apr 29. 13(1): 7037

mTORC2 interactome and localization determine aggressiveness of high-grade glioma cells through association with gelsolin.

Naphat Chantaravisoot, Piriya Wongkongkathep, Nuttiya Kalpongnukul, Narawit Pacharakullanon, Pornchai Kaewsapsak, Chaiyaboot Ariyachet, Joseph A Loo, Fuyuhiko Tamanoi, Trairak Pisitkun.

mTOR complex 2 (mTORC2) has been implicated as a key regulator of glioblastoma cell migration. However, the roles of mTORC2 in the migrational control process have not been entirely elucidated. Here, we elaborate that active mTORC2 is crucial for GBM cell motility. Inhibition of mTORC2 impaired cell movement and negatively affected microfilament and microtubule functions. We also aimed to characterize important players involved in the regulation of cell migration and other mTORC2-mediated cellular processes in GBM cells. Therefore, we quantitatively characterized the alteration of the mTORC2 interactome under selective conditions using affinity purification-mass spectrometry in glioblastoma. We demonstrated that changes in cell migration ability specifically altered mTORC2-associated proteins. GSN was identified as one of the most dynamic proteins. The mTORC2-GSN linkage was mostly highlighted in high-grade glioma cells, connecting functional mTORC2 to multiple proteins responsible for directional cell movement in GBM. Loss of GSN disconnected mTORC2 from numerous cytoskeletal proteins and affected the membrane localization of mTORC2. In addition, we reported 86 stable mTORC2-interacting proteins involved in diverse molecular functions, predominantly cytoskeletal remodeling, in GBM. Our findings might help expand future opportunities for predicting the highly migratory phenotype of brain cancers in clinical investigations.

DOI: https://doi.org/10.1038/s41598-023-33872-y
Cell Signal. 2023 May 02. pii: S0898-6568(23)00107-9. [Epub ahead of print] 110693

Inorganic pyrophosphatase 1 activates the phosphatidylinositol 3-kinase/Akt signaling to promote tumorigenicity and stemness properties in colorectal cancer.

Tianbao Niu, Jiaxin Zhu, Lujia Dong, Pengfei Yuan, Like Zhang, Dechun Liu.

  Colorectal cancer (CRC) is a common malignant tumor of the human digestive tract. Inorganic pyrophosphatase 1 (PPA1) plays an imperative role in the advancement of malignant tumors, but its function in CRC is ill-defined. In this study, we inspected the functions of PPA1 in CRC. The abundance of PPA1 in CRC tissues was analyzed by utilizing publicly available data from the The Cancer Genome Atlas and Human Protein Atlas project. Cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay were used to evaluate the viability and proliferation of CRC cells. Bioinformatics analysis was used to forecast the PPA1 related genes and signal pathways in CRC. The protein expression was examined by western blot. The xenograft model was implemented to determine the influence of PPA1 in CRC in vivo. Proliferating cell nuclear antigen, CD133, and CD44 contents in xenograft tumors were evaluated by immunohistochemistry. In the present study, we found that the PPA1 content was heightened in CRC, and the diagnostic value of PPA1 in CRC was enormous. Overexpression of PPA1 enhanced cell proliferation and stemness properties in CRC cells, while downregulation of PPA1 had the opposite effects. PPA1 promoted the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Activation of the PI3K/Akt signaling reversed the effect of PPA1 silencing on cell proliferation and stemness properties in CRC cells. Silencing of PPA1 reduced xenograft tumor growth via modulating the PI3K/Akt signaling pathway in vivo. In conclusion, PPA1 promoted cell proliferation and stemness properties in CRC by activating the PI3K/Akt signaling pathway.

Keywords:  Colorectal cancer; Inorganic pyrophosphatase 1; Phosphatidylinositol 3-kinase/Akt signaling; Stemness properties; Tumorigenicity

DOI:  https://doi.org/10.1016/j.cellsig.2023.110693
Recent Adv Antiinfect Drug Discov. 2023 Apr 27.

The Patent Landscape of mTOR and PTEN Targets.

Hailong Zhang, Yongxia Li.

   BACKGROUND: PTEN and mTOR signaling have many roles, including antiinflammatory, immunosuppressant and cancer.
OBJECTIVE: US patents were retrieved to show the current landscape of the mTOR and PTEN targets.
METHOD: PTEN and mTOR targets were analyzed by patent analysis. The U.S. granted patents from January 2003 to July 2022 were performed and analyzed.
RESULTS: The results showed that the mTOR target was more attractive in drug discovery than the PTEN target. Our findings indicated that most large global pharmaceutical companies focused the drug discovery related to the mTOR target. The present study demonstrated that mTOR and PTEN targets showed more applications in biological approaches compared to BRAF and KRAS targets. The chemical structures of the inhibitors of the mTOR target demonstrated some similar features to those of the inhibitors of KRAS targets.
CONCLUSION: At this stage, the PTEN target may not be an ideal target subjected to new drug discovery. The present study was the first one which demonstrated that the group of O=S=O may play a critical role in the chemical structures of mTOR inhibitors. It was the first time to show that a PTEN target may be suitably subjected to new therapeutic discovery efforts related to biological applications. Our findings provide a recent insight into therapeutic development for mTOR and PTEN targets.

Keywords:  Anti-inflammatory; PTEN; Patent; Patent Landscape; Targeted Drugs; mTOR

DOI:  https://doi.org/10.2174/2772434418666230427164556
Cell Death Dis. 2023 May 05. 14(5): 306

Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer.

Julia Källberg, Alexandra Harrison, Valerie March, Santa Bērziņa, Ivan Nemazanyy, Oliver Kepp, Guido Kroemer, Sophie Mouillet-Richard, Pierre Laurent-Puig, Valérie Taly, Wenjin Xiao.

The major underlying cause for the high mortality rate in colorectal cancer (CRC) relies on its drug resistance, to which intratumor heterogeneity (ITH) contributes substantially. CRC tumors have been reported to comprise heterogeneous populations of cancer cells that can be grouped into 4 consensus molecular subtypes (CMS). However, the impact of inter-cellular interaction between these cellular states on the emergence of drug resistance and CRC progression remains elusive. Here, we explored the interaction between cell lines belonging to the CMS1 (HCT116 and LoVo) and the CMS4 (SW620 and MDST8) in a 3D coculture model, mimicking the ITH of CRC. The spatial distribution of each cell population showed that CMS1 cells had a preference to grow in the center of cocultured spheroids, while CMS4 cells localized at the periphery, in line with observations in tumors from CRC patients. Cocultures of CMS1 and CMS4 cells did not alter cell growth, but significantly sustained the survival of both CMS1 and CMS4 cells in response to the front-line chemotherapeutic agent 5-fluorouracil (5-FU). Mechanistically, the secretome of CMS1 cells exhibited a remarkable protective effect for CMS4 cells against 5-FU treatment, while promoting cellular invasion. Secreted metabolites may be responsible for these effects, as demonstrated by the existence of 5-FU induced metabolomic shifts, as well as by the experimental transfer of the metabolome between CMS1 and CMS4 cells. Overall, our results suggest that the interplay between CMS1 and CMS4 cells stimulates CRC progression and reduces the efficacy of chemotherapy.

DOI: https://doi.org/10.1038/s41419-023-05806-z
Biochem J. 2023 May 05. pii: BCJ20220493. [Epub ahead of print]

The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase.

A Jane Bardwell, Madhuri Paul, Kiku C Yoneda, María D Andrade-Ludeña, Oanh T Nguyen, David Fruman, Lee Bardwell.

  IQGAP1 is a multi-domain cancer-associated protein that serves as a scaffold protein for multiple signaling pathways. Numerous binding partners have been found for the calponin homology, IQ and GAP-related domains in IQGAP1. Identification of a binding partner for its WW domain has proven elusive, however, even though a cell-penetrating peptide derived from this domain has marked anti-tumor activity. Here, using in vitro binding assays with human proteins and co-precipitation from human cells, we show that the WW domain of human IQGAP1 binds directly to the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K). In contrast, the WW domain does not bind to ERK1/2, MEK1/2, or the p85α regulatory subunit of PI3K when p85α is expressed alone. However, the WW domain is able to bind to the p110α/p85α heterodimer when both subunits are co-expressed, as well as to the mutationally activated p110α/p65α heterodimer. We present a model of the structure of the IQGAP1 WW domain, and experimentally identify key residues in the hydrophobic core and beta strands of the WW domain that are required for binding to p110α. These findings contribute to a more precise understanding of IQGAP1-mediated scaffolding, and of how IQGAP1-derived therapeutic peptides might inhibit tumorigenesis.

Keywords:  extracellular signal-regulated kinases; intracellular signaling; molecular scaffolds; phosphoinositide 3-kinase

DOI:  https://doi.org/10.1042/BCJ20220493