bims-pimaco 2021-05-23 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2021–05–23
seventeen papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Oncogenic KRAS mutations enhance amino acid uptake by colorectal cancer cells via the hippo signaling effector YAP1.
Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1.
Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation.
Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer.
Suppressing Nucleotide Exchange to Inhibit KRAS-Mutant Tumors.
Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells.
Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.
AKT but not MYC promotes reactive oxygen species-mediated cell death in oxidative culture.
The small GTPase Rab32 resides on lysosomes to regulate mTORC1 signaling.
Measuring MYC-Mediated Metabolism in Tumorigenesis.
Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer.
RAF-MEK-ERK pathway in cancer evolution and treatment.
ERK/MAPK signaling is essential for intestinal development through Wnt pathway modulation.
Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism.
A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer.
Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells.
Cost-Effectiveness of Anti-Epidermal Growth Factor Receptor Therapy Versus Bevacizumab in KRAS Wild-Type (WT), Pan-RAS WT, and Pan-RAS WT Left-Sided Metastatic Colorectal Cancer.

Mol Oncol. 2021 May 18.

Oncogenic KRAS mutations enhance amino acid uptake by colorectal cancer cells via the hippo signaling effector YAP1.

Palanivel Kandasamy, Inti Zlobec, Damian T Nydegger, Jonai Pujol Giménez, Rajesh Bhardwaj, Senji Shirasawa, Toshiyuki Tsunoda, Matthias A Hediger.

  Oncogenic KRAS mutations develop unique metabolic dependencies on nutrients to support tumor metabolism and cell proliferation. In particular, KRAS mutant cancer cells exploit amino acids (AAs) such as glutamine and leucine, to accelerate energy metabolism, redox balance through glutathione (GSH) synthesis and macromolecule biosynthesis. However, the identities of the amino acid transporters (AATs) that are prominently upregulated in KRAS mutant cancer cells, and the mechanism regulating their expression have not yet been systematically investigated. Here we report that the majority of the KRAS mutant colorectal cancer (CRC) cells upregulate selected AATs (SLC7A5/LAT1, SLC38A2/SNAT2 and SLC1A5/ASCT2), which correlates with enhanced uptake of AAs such as glutamine and leucine. Consistently, knockdown of oncogenic KRAS downregulated the expression of AATs, thereby decreasing the levels of amino acids taken up by CRC cells. Moreover, overexpression of mutant KRAS upregulated the expression of AATs (SLC7A5/LAT1, SLC38A2/SNAT2 and SLC1A5/ASCT2) in KRAS wild-type CRC cells and mouse embryonic fibroblasts (MEFs). In addition, we show that the YAP1 (Yes-associated protein 1) transcriptional coactivator accounts for increased expression of AATs and mTOR activation in KRAS mutant CRC cells. Specific knockdown of AATs by shRNAs or pharmacological blockage of AATs effectively inhibited AA uptake, mTOR activation and cell proliferation. Collectively, we conclude that oncogenic KRAS mutations enhance the expression of AATs via the hippo effector YAP1, leading to mTOR activation and CRC cell proliferation.

Keywords:  Amino acid transporters; Oncogene; SLC1A5/ASCT2; SLC38A2/SNAT2; SLC7A5/LAT1; Solute carriers

DOI:  https://doi.org/10.1002/1878-0261.12999
iScience. 2021 May 21. 24(5): 102411

Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1.

Jae Hun Shin, Jaekwang Jeong, Jungmin Choi, Jaechul Lim, Ravi K Dinesh, Jonathan Braverman, Jun Young Hong, Stephen E Maher, Maria C Amezcua Vesely, WonJu Kim, Ja-Hyun Koo, Wenwen Tang, Dianqing Wu, Holly N Blackburn, Rosa M Xicola, Xavier Llor, Omer Yilmaz, Je-Min Choi, Alfred L M Bothwell.

  Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. Genetic depletion of DKK2 in intestinal epithelial or stem cells reduced tumorigenesis and expression of the stem cell marker genes including LGR5 in a model of colitis-associated cancer. Sequential mutations in APC, KRAS, TP53, and SMAD4 genes in colonic organoids revealed a significant increase of DKK2 expression by APC knockout and further increased by additional KRAS and TP53 mutations. Moreover, DKK2 activates proto-oncogene tyrosine-protein kinse Src followed by increased LGR5 expressing cells in colorectal cancer through degradation of HNF4α1 protein. These findings suggest that DKK2 is required for colonic epithelial cells to enhance LGR5 expression during the progression of colorectal cancer.

Keywords:  Cancer; Cell Biology; Stem Cells Research

DOI:  https://doi.org/10.1016/j.isci.2021.102411
J Cell Sci. 2020 Jan 01. pii: jcs.250019. [Epub ahead of print]

Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation.

Helena Rannikmae, Samantha Peel, Simon Barry, Takao Senda, Marc de la Roche.

  The adenomatous polyposis coli (Apc) protein regulates diverse effector pathways essential for tissue homeostasis. Truncating oncogenic mutations in Apc removing its Wnt pathway and microtubule regulatory domains drives intestinal epithelia tumorigenesis. Exuberant cell proliferation is one well-established consequence of oncogenic Wnt pathway activity however, the contribution of other de-regulated molecular circuits to tumorigenesis has not been fully examined. Using in vivo and organoid models of intestinal epithelial tumorigenesis we find that Wnt pathway activity controls intestinal epithelial villi and crypt structure, morphological features lost upon Apc inactivation. While the Wnt pathway target gene c-Myc has critical roles in regulating cell proliferation and tumorigenesis, Apc specification of intestinal epithelial morphology is independent of the Wnt-responsive Myc-335 regulatory element. We further demonstrate that Apc inactivation disrupts the microtubule cytoskeleton and consequently localisation of organelles without affecting the distribution of the actin cytoskeleton and associated components. Our data indicates direct control over microtubule dynamics by Apc through an independent molecular circuit. Our study stratifies three independent Apc effector pathways in the intestinal epithelial controlling: (i) proliferation, (ii) microtubule dynamics and (iii) epithelial morphology.

Keywords:  Adenomatous polyposis coli (APC); Intestinal epithelia; Microtubule cytoskeleton; Organoids; Wnt pathway

DOI:  https://doi.org/10.1242/jcs.250019
Proc Natl Acad Sci U S A. 2021 May 25. pii: e2016904118. [Epub ahead of print]118(21):

Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer.

Derek K Cheng, Tobiloba E Oni, Jennifer S Thalappillil, Youngkyu Park, Hsiu-Chi Ting, Brinda Alagesan, Nadia V Prasad, Kenneth Addison, Keith D Rivera, Darryl J Pappin, Linda Van Aelst, David A Tuveson.

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

Keywords:  BioID; KRAS; NF1; PDAC; RSK

DOI:  https://doi.org/10.1073/pnas.2016904118
Cancer Discov. 2021 Jan;11(1): 17-19

Suppressing Nucleotide Exchange to Inhibit KRAS-Mutant Tumors.

Yulei Zhao, Jenny Y Xue, Piro Lito.

Guanine nucleotide exchange factors (GEF) control the rate-limiting step of physiologic RAS activation. In this issue of Cancer Discovery, Hofmann and colleagues describe the discovery of a selective inhibitor targeting the GEF, SOS1, along with its preclinical effects in suppressing KRAS-mutant tumor growth.See related article by Hofmann et al., p. 142.

DOI: https://doi.org/10.1158/2159-8290.CD-20-1331
Proc Natl Acad Sci U S A. 2021 May 25. pii: e2002486118. [Epub ahead of print]118(21):

Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells.

Song Chen, Caroline Chandra Tjin, Xiang Gao, Yi Xue, Haoyan Jiao, Ruilin Zhang, Mengnan Wu, Zunyu He, Jonathan Ellman, Ya Ha.

  Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase α and β (PI5P4Kα and PI5P4Kβ) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kα/β kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kαβ inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs.

Keywords:  chemical biology; lipid kinase; p53; pip4k; synthetic lethality

DOI:  https://doi.org/10.1073/pnas.2002486118
Nat Ecol Evol. 2021 May 20.

Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.

Andrew Woolston, Louise J Barber, Beatrice Griffiths, Oriol Pich, Nuria Lopez-Bigas, Nik Matthews, Sheela Rao, David Watkins, Ian Chau, Naureen Starling, David Cunningham, Marco Gerlinger.

Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRCs), but acquired resistance invariably evolves. It is unknown which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis (a transient cetuximab-induced increase in mutation generation) contributes in patients. Here, we investigate these questions in exome sequencing data from 42 baseline and progression biopsies from cetuximab-treated CRCs. Mutation loads did not increase from baseline to progression, and evidence for a contribution of adaptive mutagenesis was limited. However, the chemotherapy-induced mutational signature SBS17b was the main contributor of specific KRAS/NRAS and EGFR driver mutations that are enriched at acquired resistance. Detectable SBS17b activity before treatment predicted shorter progression-free survival and the evolution of these specific mutations during subsequent cetuximab treatment. This result suggests that chemotherapy mutagenesis can accelerate resistance evolution. Mutational signatures may be a new class of cancer evolution predictor.

DOI: https://doi.org/10.1038/s41559-021-01470-8
J Cell Sci. 2020 Jan 01. pii: jcs.239277. [Epub ahead of print]

AKT but not MYC promotes reactive oxygen species-mediated cell death in oxidative culture.

Dongqing Zheng, Jonathan H Sussman, Matthew P Jeon, Sydney T Parrish, Melanie A MacMullan, Alireza Delfarah, Nicholas A Graham.

  Oncogenes can create metabolic vulnerabilities in cancer cells. We tested how AKT and MYC affect the ability of cells to shift between respiration and glycolysis. Using immortalized mammary epithelial cells, we discovered that constitutively active AKT but not MYC induced cell death in galactose culture, where cells rely on oxidative phosphorylation for energy generation. However, the negative effects of AKT were temporary, and AKT-expressing cells recommenced growth after ∼15 days in galactose. To identify the mechanisms regulating AKT-mediated cell death, we used metabolomics and found that AKT cells dying in galactose upregulated glutathione metabolism. Proteomic profiling revealed that AKT cells dying in galactose also upregulated nonsense-mediated mRNA decay, a marker of sensitivity to oxidative stress. We therefore measured levels of reactive oxygen species (ROS) and discovered that galactose induced ROS exclusively in cells expressing AKT. Furthermore, ROS were required for galactose-induced death of AKT-expressing cells. We then confirmed that galactose induced ROS-mediated cell death in breast cancer cells with upregulated AKT signaling. These results demonstrate that AKT but not MYC restricts the flexibility of cancer cells to use oxidative phosphorylation.

Keywords:  MYC; Metabolomics; Oncogene; PI3K/AKT signaling; Proteomics; Reactive Oxygen Species

DOI:  https://doi.org/10.1242/jcs.239277
J Cell Sci. 2020 Jan 01. pii: jcs.236661. [Epub ahead of print]

The small GTPase Rab32 resides on lysosomes to regulate mTORC1 signaling.

Kristina Drizyte-Miller, Jing Chen, Hong Cao, Micah B Schott, Mark A McNiven.

  Epithelial cells such as liver-resident hepatocytes rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rabs can manifest in metabolic diseases or cancer. Rab32 is expressed in many secretory epithelial cells but its role in cellular metabolism is virtually unknown. In this study, we find that Rab32 associates with lysosomes and regulates proliferation and cell size of Hep3B hepatoma and HeLa cells. Specifically, we identify that Rab32 supports mTORC1 signaling under basal and amino acid stimulated conditions. Consistent with inhibited mTORC1, an increase in nuclear TFEB localization and lysosome biogenesis is also observed in Rab32-depleted cells. Finally, we find that Rab32 interacts with mTOR kinase and that loss of Rab32 reduces the association of mTOR and mTORC1 pathway proteins with lysosomes, suggesting that Rab32 regulates lysosomal mTOR trafficking. In summary, these findings suggest that Rab32 functions as a novel regulator of cellular metabolism through supporting mTORC1 signaling.

Keywords:  Lysosome; MTORC1; S6K; Small Rab GTPase; TFEB

DOI:  https://doi.org/10.1242/jcs.236661
Methods Mol Biol. 2021 ;2318 231-239

Measuring MYC-Mediated Metabolism in Tumorigenesis.

Hsin-Yao Tang, Aaron R Goldman, Xue Zhang, David W Speicher, Chi V Dang.

  The MYC gene regulates normal cell growth and is deregulated in many human cancers, contributing to tumor growth and progression. The MYC transcription factor activates RNA polymerases I, II, and III target genes that are considered housekeeping genes. These target genes are largely involved in ribosome biogenesis, fatty acid, protein and nucleotide synthesis, nutrient influx or metabolic waste efflux, glycolysis, and glutamine metabolism. MYC's function as a driver of cell growth has been revealed through RNA sequencing, genome-wide chromatin immunoprecipitation, proteomics, and importantly metabolomics, which is highlighted in this chapter.

Keywords:  Cancer metabolism; MYC; Mass spectrometry; Metabolomics; Transcription

DOI:  https://doi.org/10.1007/978-1-0716-1476-1_11
Theranostics. 2021 ;11(13): 6560-6572

Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer.

Kai-Li Zhang, Wen-Wei Zhu, Sheng-Hao Wang, Chao Gao, Jun-Jie Pan, Zun-Guo Du, Lu Lu, Hu-Liang Jia, Qiong-Zhu Dong, Jin-Hong Chen, Ming Lu, Lun-Xiu Qin.

  Rationale: Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. Methods: The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The in vivo efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. Results: In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Conclusion: Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.

Keywords:  HGF; SREBP2; cholesterol biosynthesis; colorectal cancer; liver metastasis

DOI:  https://doi.org/10.7150/thno.55609
Semin Cancer Biol. 2021 May 13. pii: S1044-579X(21)00138-3. [Epub ahead of print]

RAF-MEK-ERK pathway in cancer evolution and treatment.

Rahim Ullah, Qing Yin, Aidan H Snell, Lixin Wan.

  The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAFV600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors.

Keywords:  Cancer; ERK; MAPK; MEK; RAF

DOI:  https://doi.org/10.1016/j.semcancer.2021.05.010
Development. 2020 Jan 01. pii: dev.185678. [Epub ahead of print]

ERK/MAPK signaling is essential for intestinal development through Wnt pathway modulation.

Gaigai Wei, Na Gao, Jiwei Chen, Lingling Fan, Zhiyang Zeng, Ganglong Gao, Liang Li, Guojiu Fang, Kewen Hu, Xiufeng Pang, Heng-Yu Fan, Hans Clevers, Mingyao Liu, Xueli Zhang, Dali Li.

  Homeostasis of intestinal stem cells (ISCs) is maintained by the orchestration of niche factors and intrinsic signaling networks. Here we found that deletion of Erk1/2 in intestinal epithelial cells at embryonic stages resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 results in defects in secretory cell differentiation as well as impaired mesenchymal cell proliferation and maturation. Deletion of Erk1/2 strongly activated Wnt signaling through both cell-autonomous and non-autonomous mechanisms. In epithelial cells, Erk1/2 depletion resulted in loss of the feedback regulation leading to Ras/Raf cascade activation which transactivated Akt activity to stimulate the mTor and Wnt/β-catenin pathways. Moreover, Erk1/2 deficiency reduced the Indian hedgehog level and the expression of downstream pathway components including mesenchymal Bmp4, a Wnt suppressor in intestines. Inhibition of mTor signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged mutant mice life span. These data demonstrate that Erk/Mapk signaling functions as a key modulator of Wnt signaling through coordination of epithelial-mesenchymal interactions during intestinal development.

Keywords:  Hedgehog signaling; Intestinal stem cell; MAPK; Mesenchymal cell; Wnt signaling

DOI:  https://doi.org/10.1242/dev.185678
Cell Commun Signal. 2021 May 20. 19(1): 57

Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism.

Mehrshad Sadria, Anita T Layton.

   BACKGROUND: Cells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of perturbations. In tissues a deficit of these mechanisms is commonly associated with cellular aging and diseases, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as being able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and energy balance in mammals.
METHODS: To understand the complex interactions of these signalling pathways and environmental signals, and how those interactions may impact lifespan and health-span, we have developed a computational model of metabolic signalling pathways. Specifically, the model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and the amino acid sensors such as sestrin, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+ -consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α.
RESULTS: The model simulates the interactions among key regulators such as AKT, mTORC1, AMPK, NAD+ , and SIRT, and predicts their dynamics. Key findings include the clinically important role of PRAS40 and diet in mTORC1 inhibition, and a potential link between SIRT1-activating compounds and premature autophagy. Moreover, the model captures the exquisite interactions of leucine, sestrin2, and arginine, and the resulting signal to the mTORC1 pathway. These results can be leveraged in the development of novel treatment of cancers and other diseases.
CONCLUSIONS: This study presents a state-of-the-art computational model for investigating the interactions among signaling pathways and environmental stimuli in growth, ageing, metabolism, and diseases. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and assess their functional implications on longevity and ageing-related diseases. Video Abstract.

Keywords:  Ageing; Autophagy; Growth factor signaling; Longevity; MTOR; Metabolism; NAD+ ; Proliferation; Sirtuins; System biology

DOI:  https://doi.org/10.1186/s12964-021-00706-1
Protein Sci. 2021 May 19.

A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer.

David E Heppner, Michael J Eck.

Precision oncology is premised on identifying and drugging proteins and pathways that drive tumorigenesis or are required for survival of tumor cells. Across diverse cancer types, signaling pathway emanating from receptor tyrosine kinases on the cell surface to RAS and the MAP kinase pathway is the most frequent target of oncogenic mutations, and key proteins in this signaling axis including EGFR, SHP2, RAS, BRAF and MEK have long been a focus in cancer drug discovery. In this review, we provide an overview of historical and recent efforts to develop inhibitors targeting these nodes with an emphasis on the role that an understanding of protein structure and regulation has played in inhibitor discovery and characterization. Beyond its well-established role in structure-based drug design, structural biology has revealed mechanisms of allosteric regulation, distinct effects of activating oncogenic mutations, and other vulnerabilities that have opened new avenues in precision cancer drug discovery. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/pro.4125
Sci Rep. 2021 May 18. 11(1): 10487

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells.

Abdelnour H Alhourani, Tia R Tidwell, Ansooya A Bokil, Gro V Røsland, Karl Johan Tronstad, Kjetil Søreide, Hanne R Hagland.

Cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg. However, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Metformin, a metabolic drug commonly used to treat type 2 diabetes, has been associated with lower cancer incidence, although studies are inconclusive concerning effectiveness of the drug in treatment or cancer prevention. The aim of this study was to determine how glucose concentration influences cancer cells' response to metformin, highlighting why metformin studies are inconsistent. We used two colorectal cancer cell lines with different growth rates and clinically achievable metformin concentrations. We found that fast growing SW948 are more glycolytic in terms of metabolism, while the slower growing SW1116 are reliant on mitochondrial respiration. Both cell lines show inhibitory growth after metformin treatment under physiological glucose conditions, but not in high glucose conditions. Furthermore, SW1116 converges with SW948 at a more glycolytic phenotype after metformin treatment. This metabolic shift is supported by changed GLUT1 expression. Thus, cells having different metabolic phenotypes, show a clear differential response to metformin treatment based on glucose concentration. This demonstrates the importance of growth conditions for experiments or clinical studies involving metabolic drugs such as metformin.

DOI: https://doi.org/10.1038/s41598-021-89861-6
Front Oncol. 2021 ;11 651299

Cost-Effectiveness of Anti-Epidermal Growth Factor Receptor Therapy Versus Bevacizumab in KRAS Wild-Type (WT), Pan-RAS WT, and Pan-RAS WT Left-Sided Metastatic Colorectal Cancer.

Shing Fung Lee, Horace C W Choi, Sik Kwan Chan, Ka On Lam, Victor H F Lee, Irene O L Wong, Chi Leung Chiang.

   Objectives: We aimed to compare the economic value of chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) against chemotherapy with bevacizumab (Bev, an anti-vascular endothelial growth factor mAb) as first-line treatment in KRAS wild-type (WT), pan-RAS WT and pan-RAS WT left-sided metastatic colorectal cancer (mCRC) patients from the Hong Kong societal perspective.
Materials and Methods: We developed Markov models and 10-year horizon to estimate costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) of chemotherapy plus anti-EGFR therapy against chemotherapy plus Bev in KRAS WT, pan-RAS WT, and pan-RAS WT left-sided mCRC. We considered two times of the local gross domestic product per capita (GDPpc) as the willingness-to-pay (WTP) threshold (2× GDPpc; US$97,832).
Results: Adding anti-EGFR mAb to chemotherapy provides additional 0.24 (95% confidence interval [CI] 0.19-0.29), 0.32 (95% CI 0.27-0.37), and 0.57 (95% CI 0.49-0.63) QALY compared to adding Bev in KRAS WT, pan-RAS WT, and left-sided pan-RAS WT mCRC populations respectively. The corresponding ICER is US$106,847 (95% CI 87,806-134,523), US$88,565 (95% CI 75,678-105,871), US$76,537 (95% CI 67,794-87,917) per QALY gained, respectively.
Conclusions: Anti-EGFR therapy is more cost-effective than Bev as a first-line targeted therapy in left-sided pan-RAS WT and pan-RAS WT, with ICER <US$100,000/QALY, compared to KRAS WT mCRC population.

Keywords:  colorectal cancer; decision-making; economic evaluation; economic evidence; simulation models

DOI:  https://doi.org/10.3389/fonc.2021.651299