bims-pimaco 2022-10-23 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2022–10–23
ten papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers.
Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.
PI3K and AKT at the Interface of Signaling and Metabolism.
Inhibition of RAS-driven signaling and tumorigenesis with a pan-RAS monobody targeting the Switch I/II pocket.
Class I PI3K Biology.
Selective vulnerability of ARID1A deficient colon cancer cells to combined radiation and ATR-inhibitor therapy.
Autophagy: Dual roles and perspective for clinical treatment of colorectal cancer.
A Noncovalent KRASG12D Inhibitor Shows Potent and Selective Activity.
Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer.
Association between dietary intake of fatty acids and colorectal cancer, a case-control study.

Sci Signal. 2022 Oct 18. 15(756): eabj3490

Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers.

Deborah Y Moss, Christopher McCann, Emma M Kerr.

Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The constitutive activity of mutant KRAS and its downstream signaling pathways induces metabolic rewiring in tumor cells that can promote resistance to existing therapeutics. In this review, we discuss the metabolic pathways that are altered in response to treatment and those that can, in turn, alter treatment efficacy, as well as the role of metabolism in the tumor microenvironment (TME) in dictating the therapeutic response in KRAS-driven cancers. We highlight metabolic targets that may provide clinical opportunities to overcome therapeutic resistance and improve survival in patients with these aggressive cancers.

DOI: https://doi.org/10.1126/scisignal.abj3490
PLoS One. 2022 ;17(10): e0276579

Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.

Ahmet Hatipoglu, Deepak Menon, Talia Levy, Maria A Frias, David A Foster.

Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt-a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase-indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.

DOI: https://doi.org/10.1371/journal.pone.0276579
Curr Top Microbiol Immunol. 2022 ;436 311-336

PI3K and AKT at the Interface of Signaling and Metabolism.

Giovanni Solinas, Barbara Becattini.

  The PI3K/AKT signaling module is recruited by several receptors implicated in maintaining tissue and metabolic homeostasis and signaling pathways controlling immune responses. Constitutive activation of PI3K/AKT signaling leads to tissue overgrowth and is frequently observed in cancer cells, whereas reduced PI3K/AKT signaling is associated with diabetes and growth defects. Thus, a critical roadblock to effective PI3K-targeted therapy comes from the crucial role of PI3K/AKT signaling in systemic metabolic homeostasis. This chapter describes the role of PI3K/AKT in insulin signaling and metabolic homeostasis and the interplay between insulin action and metabolic feedback loops that cause resistance to PI3K-targeted therapies. Furthermore, we provide examples of insulin-independent roles for PI3K/AKT in metabolic homeostasis, and some generalizations on the action of PI3K/AKT signaling at the interface of signaling and metabolism are derived. Finally, the specific roles for different class I PI3K isoforms in controlling systemic metabolic homeostasis and energy balance are discussed. We conclude that defining the functional specificities and redundancies of different class I PI3K isoforms in pathways driving disease and controlling metabolic homeostasis is fundamental to develop novel PI3K-targeted therapies.

Keywords:  Cancer; Diabetes; Growth; Immunometabolism; Insulin; Metabolic Inflammation; Obesity

DOI:  https://doi.org/10.1007/978-3-031-06566-8_13
Proc Natl Acad Sci U S A. 2022 Oct 25. 119(43): e2204481119

Inhibition of RAS-driven signaling and tumorigenesis with a pan-RAS monobody targeting the Switch I/II pocket.

Lauren Wallon, Imran Khan, Kai Wen Teng, Akiko Koide, Mariyam Zuberi, Jianping Li, Gayatri Ketavarapu, Nathaniel J Traaseth, John P O'Bryan, Shohei Koide.

  RAS mutants are major therapeutic targets in oncology with few efficacious direct inhibitors available. The identification of a shallow pocket near the Switch II region on RAS has led to the development of small-molecule drugs that target this site and inhibit KRAS(G12C) and KRAS(G12D). To discover other regions on RAS that may be targeted for inhibition, we have employed small synthetic binding proteins termed monobodies that have a strong propensity to bind to functional sites on a target protein. Here, we report a pan-RAS monobody, termed JAM20, that bound to all RAS isoforms with nanomolar affinity and demonstrated limited nucleotide-state specificity. Upon intracellular expression, JAM20 potently inhibited signaling mediated by all RAS isoforms and reduced oncogenic RAS-mediated tumorigenesis in vivo. NMR and mutation analysis determined that JAM20 bound to a pocket between Switch I and II, which is similarly targeted by low-affinity, small-molecule inhibitors, such as BI-2852, whose in vivo efficacy has not been demonstrated. Furthermore, JAM20 directly competed with both the RAF(RBD) and BI-2852. These results provide direct validation of targeting the Switch I/II pocket for inhibiting RAS-driven tumorigenesis. More generally, these results demonstrate the utility of tool biologics as probes for discovering and validating druggable sites on challenging targets.

Keywords:  drug discovery; synthetic binding protein; target validation; tool biologic

DOI:  https://doi.org/10.1073/pnas.2204481119
Curr Top Microbiol Immunol. 2022 ;436 3-49

Class I PI3K Biology.

Tihitina Y Aytenfisu, Hannah M Campbell, Mayukh Chakrabarti, L Mario Amzel, Sandra B Gabelli.

  This chapter is an introduction to phosphoinositide 3-kinases (PI3K), with class I PI3Ks as the central focus. First, the various PI3K isoforms in class I are presented with emphasis on their overall structure, subunits, subunit constitutive domains, domain-domain interactions, and functional relevance. This structural analysis is followed by a comprehensive history of seminal investigations into PI3K activity. Next, we highlight the divergent roles of the isoforms: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. This section details signaling pathways in which these PI3K isoforms are involved, including the key upstream regulators of PI3K activity and some downstream cellular effects. Nodes of the PI3K pathway are also presented. Inhibitors of some isoforms are discussed to give an overview of the basis of some immunotherapies that are being used to target cell signaling. Finally, the chapter ends with a discussion of the dysregulation of PI3Ks in diseases including APDS, asthma, arthritis, and oncogenic mutations.

Keywords:  APDS; Arthritis; Asthma; B-cell signaling; Chronic inflammation; Class I PI3Ks; Oncogenic mutation; PI3K; Phosphoinositide-3-kinase; RTK signaling; Ras signaling; T-cell signaling; p101; p110β; p110γ; p110δ; p84; pl10α

DOI:  https://doi.org/10.1007/978-3-031-06566-8_1
Front Oncol. 2022 ;12 999626

Selective vulnerability of ARID1A deficient colon cancer cells to combined radiation and ATR-inhibitor therapy.

Shan Xu, Ali Sak, Ben Niedermaier, Yasin Bahadir Erol, Michael Groneberg, Emil Mladenov, MingWei Kang, George Iliakis, Martin Stuschke.

  ARID1A is frequently mutated in colorectal cancer (CRC) cells. Loss of ARID1A function compromises DNA damage repair and increases the reliance of tumor cells on ATR-dependent DNA repair pathways. Here, we investigated the effect of ionizing radiation (IR), in combination with ATR inhibitors (ATRi) in CRC cell lines with proficient and deficient ARID1A. The concept of selective vulnerability of ARID1A deficient CRC cells to ATRi was further tested in an ex vivo system by using the ATP-tumor chemosensitivity assay (ATP-TCA) in cells from untreated CRC patients, with and without ARID1A expression. We found selective sensitization upon ATRi treatment as well as after combined treatment with IR (P<0.001), especially in ARID1A deficient CRC cells (P <0.01). Knock-down of ARID1B further increased the selective radiosensitivity effect of ATRi in ARID1A negative cells (P<0.01). Mechanistically, ATRi abrogates the G2 checkpoint (P<0.01) and homologous recombination repair (P<0.01) in ARID1A deficient cells. Most importantly, ex-vivo experiments showed that ATRi had the highest radiosensitizing effect in ARID1A negative cells from CRC patients. Collectively, our results generate pre-clinical and clinical mechanistic rationale for assessing ARID1A defects as a biomarker for ATR inhibitor response as a single agent, or in a synthetic lethal approach in combination with IR.

Keywords:  ARID1A; ATR; SWI/SNF; colorectal cancer; synthetic lethality

DOI:  https://doi.org/10.3389/fonc.2022.999626
Biochimie. 2022 Oct 13. pii: S0300-9084(22)00268-1. [Epub ahead of print]

Autophagy: Dual roles and perspective for clinical treatment of colorectal cancer.

Yabin Zhang, Haiyan Li, Liang Lv, Kefeng Lu, Huihui Li, Wenli Zhang, Tao Cui.

  Colorectal cancer (CRC) raises concerns to people because of its high recurrence and metastasis rate, diagnosis challenges, and poor prognosis. Various studies have shown the association of altered autophagy with tumorigenesis, tumor-stroma interactions, and resistance to cancer therapy in CRC. Autophagy is a highly conserved cytosolic catabolic process in eukaryotes that plays distinct roles in CRC occurrence and progression. In early tumorigenesis, autophagy may inhibit tumor growth through diverse mechanisms, whereas it exhibits a tumor promoting function in CRC progression. This different functions of autophagy in CRC occurrence and progression make developing therapies targeting autophagy complicated. In this review, we discuss the classification and process of autophagy as well as its dual roles in CRC, functions in the tumor microenvironment, cross-talk with apoptosis, and potential usefulness as a CRC therapeutic target.

Keywords:  Autophagy; Chemo-/immuno-therapy; Colorectal cancer; Tumor microenvironment; Tumor promoter; Tumor suppressor

DOI:  https://doi.org/10.1016/j.biochi.2022.10.004
Cancer Discov. 2022 Oct 21. OF1

A Noncovalent KRASG12D Inhibitor Shows Potent and Selective Activity.

MRTX1133 is a high-affinity, selective, and potent KRASG12D inhibitor with antitumor efficacy.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-186
Oncotarget. 2022 Oct 19. 13 1140-1152

Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer.

Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Amrendra K Ajay, Larissa Camila Ribeiro de Souza, Minghua Cao, Yueming Luo, Petra Hoegger, Carmen M Ribas, Jurandir M Ribas-Filho, Osvaldo Malafaia, Reinhard Lissner, Li-Li Hsiao, Ana Maria Waaga-Gasser.

  Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression. We have recently provided evidence for upregulation of PDGF expression in UICC stage I-IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. The present study sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC. Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRβ, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors. Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. We then analyzed several CRC cell lines for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 protein expression and found these receptors to be variably expressed amongst the investigated cell lines. Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor. Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.

Keywords:  EGFR; PDGF; VEGFR; bypassed signaling; colorectal cancer

DOI:  https://doi.org/10.18632/oncotarget.28281
Front Nutr. 2022 ;9 856408

Association between dietary intake of fatty acids and colorectal cancer, a case-control study.

Soheila Shekari, Soroor Fathi, Zahra Roumi, Mohammad Esmail Akbari, Shirin Tajadod, Maryam Afsharfar, Naeemeh Hasanpour Ardekanizadeh, Fatemeh Bourbour, Seyed Ali Keshavarz, Mahtab Sotoudeh, Maryam Gholamalizadeh, Shiva Nemat Gorgani, Hanieh Shafaei Kachaei, Atiyeh Alizadeh, Saeid Doaei.

   Background: The association of dietary fat and colorectal cancer (CRC) was frequently reported. However, few studies assessed the effects of different types of dietary fats on CRC. This study aimed to investigate the association between intakes of different types of dietary fatty acids with colorectal cancer risk.
Methods: This case-control study was conducted on 480 participants including 160 CRC cases and 320 healthy controls in Firoozgar Hospital, Tehran, Iran. The intake of dietary fatty acids of the participants was assessed using a semi quantitative food frequency questionnaire (FFQ).
Results: The mean intake of cholesterol (273.07 ± 53.63 vs. 254.17 ± 61.12, P = 0.001), polyunsaturated fatty acids (PUFA) (16.54 ± 4.20 vs. 15.41 ± 4.44, P = 0.012), and calorie (2,568.76 ± 404.48 vs. 2,493.38 ± 176.03, P = 0.006) was higher and the mean intake of oleic acid (5.59 ± 3.17 vs. 8.21 ± 5.46) and linoleic acid (6.03 ± 3.44 vs. 7.02 ± 4.08, P = 0.01) was lower in the case group compared to the control group. An inverse association was found between colorectal cancer (CRC) and dietary intake of oleic acid (OR: 0.85, CI 95% 0.80-0.90, P = 0.001), linoleic acid (OR: 0.85, CI 95% 0.78-0.93, P = 0.001), and α-linolenic acid (OR: 0.75, CI 95% 0.57-0.98, P = 0.04). The association remained significant after adjusting for age and sex, sleep, smoking, and alcohol consumption, and BMI.
Conclusions: The results of this study support a protective effect of oleic acid, linoleic acid, and α-linolenic acid against CRC. Further longitudinal studies are warranted to confirm these results.

Keywords:  cancer; colorectal cancer risk; dietary intake; fat; fatty acids

DOI:  https://doi.org/10.3389/fnut.2022.856408