bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2022–07–31
ten papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research
  1. PI3K drives the de novo synthesis of coenzyme A from vitamin B5.
  2. Prognostic Value of KRAS Mutations in Colorectal Cancer Patients.
  3. Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice.
  4. Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer.
  5. EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.
  6. Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.
  7. Beyond controlling cell size: functional analyses of S6K in tumorigenesis.
  8. Akt protein boosts cancer metabolism through a two-pronged attack.
  9. Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.
  10. Colorectal cancer chemoprevention: is aspirin still in the game?
  1. Nature. 2022 Jul 27.
    PI3K drives the de novo synthesis of coenzyme A from vitamin B5.
    Christian C Dibble, Samuel A Barritt, Grace E Perry, Evan C Lien, Renee C Geck, Sarah E DuBois-Coyne, David Bartee, Thomas T Zengeya, Emily B Cohen, Min Yuan, Benjamin D Hopkins, Jordan L Meier, John G Clohessy, John M Asara, Lewis C Cantley, Alex Toker.
      In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis1. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling2,3. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells4,5 and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate)6,7. We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT8. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK49 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K-PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.
    DOI:  https://doi.org/10.1038/s41586-022-04984-8
  2. Cancers (Basel). 2022 Jul 07. pii: 3320. [Epub ahead of print]14(14):
    Prognostic Value of KRAS Mutations in Colorectal Cancer Patients.
    Asimina Koulouridi, Michaela Karagianni, Ippokratis Messaritakis, Maria Sfakianaki, Alexandra Voutsina, Maria Trypaki, Maria Bachlitzanaki, Evangelos Koustas, Michalis V Karamouzis, Anastasios Ntavatzikos, Anna Koumarianou, Nikolaos Androulakis, Dimitrios Mavroudis, Maria Tzardi, John Souglakos.
      Colorectal cancer (CRC) remains a major public health issue. The detection of parameters that affect CRC prognosis is of great significance. KRAS mutations, play a crucial role in tumorigenesis with a strong predictive value. KRAS-mutated stage-IV CRC patients gain no benefit of the anti-EGFR therapy. The KRAS G12C mutation subtype is under investigation for treatment regimens. The present study aimed to detect various RAS mutations in a cohort of 578 RAS-mutated CRC patients; 49% of them had de novo metastatic disease; 60% were male; 71.4% had left-sided tumors; and 94.6% had a good performance status. KRAS mutations were detected in 93.2% of patients, with KRAS G12D being the most common subtype (30.1%). KRAS mutations presented shorter progression-free (PFS) and overall survival (OS), compared with NRAS mutations, although not significantly (PFS: 13.8 vs. 18.5 months; p = 0.552; OS: 53.1 vs. 60.9 months; p = 0.249). KRAS G12D mutations presented better OS rates (p = 0.04). KRAS G12C mutation, even though not significantly, presented worse PFS and OS rates. KRAS exon 3 and 4 mutations presented different PFS and OS rates, although these were not significant. Concluding, KRAS G12D and G12C mutations lead to better and worst prognosis, respectively. Further studies are warranted to validate such findings and their possible therapeutic implication.
    Keywords:  KRAS; colorectal cancer; mutations; prognosis
    DOI:  https://doi.org/10.3390/cancers14143320
  3. Nat Biotechnol. 2022 Jul 25.
    Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice.
    Bhairavi Tolani, Anna Celli, Yanmin Yao, Yong Zi Tan, Richard Fetter, Christina R Liem, Adam J de Smith, Thamiya Vasanthakumar, Paola Bisignano, Adam D Cotton, Ian B Seiple, John L Rubinstein, Marco Jost, Jonathan S Weissman.
      Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. Unexpectedly, potency of 249C varies with the identity of the Ras driver mutation, with the highest potency for KRASG13D and G12V both in vitro and in vivo, highlighting a mutant-specific dependence on macropinocytosis and lysosomal pH. Indeed, 249C potently inhibits tumor growth without adverse side effects in mouse xenografts of KRAS-driven lung and colon cancers. A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.
    DOI:  https://doi.org/10.1038/s41587-022-01386-z
  4. Cancer Treat Rev. 2022 Jun 30. pii: S0305-7372(22)00102-5. [Epub ahead of print]109 102433
    Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer.
    Jorien B E Janssen, Jan Paul Medema, Elske C Gootjes, Daniele V F Tauriello, Henk M W Verheul.
      RAS genes are the most frequently mutated oncogenes in cancer. These mutations occur in roughly half of the patients with colorectal cancer (CRC). RAS mutant tumors are resistant to therapy with anti-EGFR monoclonal antibodies. Therefore, patients with RAS mutant CRC currently have few effective therapy options. RAS mutations lead to constitutively active RAS GTPases, involved in multiple downstream signaling pathways. These alterations are associated with a tumor microenvironment (TME) that drives immune evasion and disease progression by mechanisms that remain incompletely understood. In this review, we focus on the available evidence in the literature explaining the potential effects of RAS mutations on the CRC microenvironment. Ongoing efforts to influence the TME by targeting mutant RAS and thereby sensitizing these tumors to immunotherapy will be discussed as well.
    Keywords:  Colorectal cancer; Immunotherapy; RAS mutations; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ctrv.2022.102433
  5. Curr Biol. 2022 Jul 19. pii: S0960-9822(22)01104-6. [Epub ahead of print]
    EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.
    Chenge Zhang, Yinhua Jin, Marco Marchetti, Mitchell R Lewis, Omar T Hammouda, Bruce A Edgar.
      EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.
    Keywords:  Ets21C; ISC; Pointed; intestinal stem cell; mitochondrial biogenesis; mtTFB2; proliferation
    DOI:  https://doi.org/10.1016/j.cub.2022.07.003
  6. Clin Cancer Res. 2022 Jul 26. OF1-OF16
    Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.
    Erika Durinikova, Nicole M Reilly, Kristi Buzo, Elisa Mariella, Rosaria Chilà, Annalisa Lorenzato, João M L Dias, Gaia Grasso, Federica Pisati, Simona Lamba, Giorgio Corti, Andrea Degasperi, Carlotta Cancelliere, Gianluca Mauri, Pietro Andrei, Michael Linnebacher, Silvia Marsoni, Salvatore Siena, Andrea Sartore-Bianchi, Serena Nik-Zainal, Federica Di Nicolantonio, Alberto Bardelli, Sabrina Arena.
       PURPOSE: Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored.
    EXPERIMENTAL DESIGN: We challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs.
    RESULTS: We found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines.
    CONCLUSIONS: In conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0875
  7. Cell Death Dis. 2022 Jul 25. 13(7): 646
    Beyond controlling cell size: functional analyses of S6K in tumorigenesis.
    Xueji Wu, Wei Xie, Wenxuan Xie, Wenyi Wei, Jianping Guo.
      As a substrate and major effector of the mammalian target of rapamycin complex 1 (mTORC1), the biological functions of ribosomal protein S6 kinase (S6K) have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, and protein synthesis. However, accumulating evidence implies that diverse stimuli and upstream regulators modulate S6K kinase activity, leading to the activation of a plethora of downstream substrates for distinct pathobiological functions. Beyond controlling cell size, S6K simultaneously plays crucial roles in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals. Thus, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for S6K and shed light on S6K as a potential therapeutic target for cancers.
    DOI:  https://doi.org/10.1038/s41419-022-05081-4
  8. Nature. 2022 Jul 27.
    Akt protein boosts cancer metabolism through a two-pronged attack.
    Philipp Poeller, Almut Schulze.
      
    Keywords:  Biochemistry; Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-022-01603-4
  9. Cancers (Basel). 2022 Jul 11. pii: 3374. [Epub ahead of print]14(14):
    Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.
    Leslie Cuellar-Vite, Kristen L Weber-Bonk, Fadi W Abdul-Karim, Christine N Booth, Ruth A Keri.
      The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling.
    Keywords:  FAK; TNBC; collateral sensitivity; defactinib; focal adhesion kinase; intrinsic resistance; mTORC1; rapamycin; triple negative breast cancer
    DOI:  https://doi.org/10.3390/cancers14143374
  10. Cancer Biol Ther. 2022 Dec 31. 23(1): 446-461
    Colorectal cancer chemoprevention: is aspirin still in the game?
    Adrien Grancher, Pierre Michel, Frederic Di Fiore, David Sefrioui.
      Screening strategies have demonstrated their potential for decreasing the incidence and mortality of cancers, particularly that of colorectal cancer (CRC). Another strategy that has been developed to reduce CRC occurrence is the use of chemoprevention agents. Among them, aspirin is the most promising. Aspirin acts in colorectal tumourigenesis through several mechanisms, either directly in tumor cells or in their microenvironment, such as through its anti-inflammatory activity or its effect on the modulation of platelet function. Many retrospective studies, as well as follow-up of large cohorts from trials with primary cardiovascular end points, have shown that long-term treatment with daily low-dose aspirin decreases the incidence of adenomas and colorectal cancers. Therefore, aspirin is currently recommended by the United States Preventive Services Task Force (USPSTF) for primary prevention of CRC in all patients aged 50 to 59 with a 10-y risk of cardiovascular events greater than 10%. Furthermore, several studies have also reported that long-term aspirin treatment taking after CRC resection decreases recurrence risk and increases overall survival, especially in patients with PIK3CA-mutated tumors. This review summarizes current knowledge on the pathophysiological mechanisms of aspirin chemoprevention, discusses the primary clinical results on CRC prevention and highlights the potential biomarkers identified to predict aspirin efficacy.
    Keywords:  Aspirin; PIK3CA mutation; colorectal cancer
    DOI:  https://doi.org/10.1080/15384047.2022.2104561
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