bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2022‒04‒24
nine papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research
  1. The oncogenic PI3K-induced transcriptomic landscape reveals key functions in splicing and gene expression regulation.
  2. AKT mutant allele-specific activation dictates pharmacologic sensitivities.
  3. Mutation patterns and prognostic analysis of BRAF/KRAS/PIK3CA in colorectal cancer.
  4. A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer.
  5. KRAS: A Druggable Target in Colon Cancer Patients.
  6. Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK.
  7. Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.
  8. Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors.
  9. PTEN in cancer associated fibroblasts.
  1. Cancer Res. 2022 Apr 20. pii: canres.CAN-22-0446-E.2022. [Epub ahead of print]
    The oncogenic PI3K-induced transcriptomic landscape reveals key functions in splicing and gene expression regulation.
    Erik Ladewig, Flavia Michelini, Komal Jhaveri, Pau Castel, Javier Carmona, Lauren Fairchild, Adler G Zuniga, Amaia Arruabarrena-Aristorena, Emiliano Cocco, Ryan Blawski, Srushti Kittane, Yuhan Zhang, Mirna Sallaku, Laura Baldino, Vasilis Hristidis, Sarat Chandarlapaty, Omar Abdel-Wahab, Christina Leslie, Maurizio Scaltriti, Eneda Toska.
      The PI3K pathway regulates proliferation, survival, and metabolism and is frequently activated across human cancers. A comprehensive elucidation of how this signaling pathway controls transcriptional and co-transcriptional processes could provide new insights into the key functions of PI3K signaling in cancer. Here, we undertook a transcriptomic approach to investigate genome-wide gene expression and transcription factor (TF) activity changes, as well as splicing and isoform usage dynamics, downstream of PI3K. These analyses uncovered widespread alternatively spliced (AS) isoforms linked to proliferation, metabolism, and splicing in PIK3CA mutant cells, which were reversed by inhibition of PI3Kα. Analysis of paired tumor biopsies from PIK3CA-mutated breast cancer patients undergoing treatment with PI3Kα inhibitors identified widespread splicing alterations that affect specific isoforms in common with the preclinical models, and these alterations, namely PTK2/FRNK and AFMID isoforms, were validated as functional drivers of cancer cell growth or migration. Mechanistically, isoform-specific splicing factors mediated PI3K-dependent RNA splicing. Treatment with splicing inhibitors rendered breast cancer cells more sensitive to the PI3Kα inhibitor alpelisib, resulting in greater growth inhibition than alpelisib alone. This study provides the first comprehensive analysis of widespread splicing alterations driven by oncogenic PI3K in breast cancer. The atlas of PI3K-mediated splicing programs establishes a key role for the PI3K pathway in regulating splicing, opening new avenues for exploiting PI3K signaling as a therapeutic vulnerability in breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0446
  2. Nat Commun. 2022 Apr 19. 13(1): 2111
    AKT mutant allele-specific activation dictates pharmacologic sensitivities.
    Tripti Shrestha Bhattarai, Tambudzai Shamu, Alexander N Gorelick, Matthew T Chang, Debyani Chakravarty, Elena I Gavrila, Mark T A Donoghue, JianJong Gao, Swati Patel, Sizhi Paul Gao, Margaret H Reynolds, Sarah M Phillips, Tara Soumerai, Wassim Abida, David M Hyman, Alison M Schram, David B Solit, Lillian M Smyth, Barry S Taylor.
      AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.
    DOI:  https://doi.org/10.1038/s41467-022-29638-1
  3. J Clin Lab Anal. 2022 Apr 18. e24444
    Mutation patterns and prognostic analysis of BRAF/KRAS/PIK3CA in colorectal cancer.
    Chengfeng Wang, Diling Pan.
      BACKGROUND AND OBJECTIVE: Aberrant gene expression and abnormal signaling pathways often occur in patients with colorectal cancer, in which mutations in B-Raf Proto-Oncogene (BRAF), KRAS Proto-Oncogene (KRAS), and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) are quite common. In this study, the relationship between BRAF, KRAS, and PIK3CA mutations and clinicopathologic features and prognosis of colorectal cancer patients was investigated.METHODS: One hundred and fifty patients with colorectal cancer admitted to Affiliated people's Hospital (Fujian Provincial People's Hospital), Fujian University of Traditional Chinese Medicine were collected and grouped according to the mutation patterns of BRAF, KRAS, and PIK3CA. The association between BRAF, KRAS, and PIK3CA mutations and pathological factors (age, sex, etc.) was analyzed using the Chi-square test. Subsequently, survival analysis was performed to screen the impact factors of overall survival time by Kaplan-Meier (K-M) curve, and Cox regression model was established for the selected factors.
    RESULTS: BRAF, KRAS, and PIK3CA mutations were not associated with age, sex, and alcoholism. K-M curve and log-rank test results demonstrated that among the factors included in this study, overall survival rate of colorectal cancer patients was only associated with mutation factors. The prognosis of KRAS+/PIK3CA-/BRAF-mutant and KRAS-/PIK3CA-/BRAF+mutant patients was better than that of KRAS+/PIK3CA+/BRAF-mutant patients.
    CONCLUSION: The mutant patterns of BRAF, KRAS, and PIK3CA were not related to the general and clinicopathological features of patients. The mutant pattern could be used as an independent prognostic factor for colorectal cancer.
    Keywords:  BRAF mutation; KRAS mutation; PIK3CA mutation; colorectal cancer; prognostic analysis
    DOI:  https://doi.org/10.1002/jcla.24444
  4. Biomedicines. 2022 Apr 06. pii: 859. [Epub ahead of print]10(4):
    A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer.
    Jung Kyu Choi, Ihn-Sil Kwak, Sae-Bom Yoon, Heeyeong Cho, Byoung-San Moon.
      Cancer stem cells (CSCs) are a tumor cell subpopulation that drives tumor progression and metastasis, leading to a poor overall survival of patients. In colorectal cancer (CRC), the hyper-activation of Wnt/β-catenin signaling by a mutation of both adenomatous polyposis coli (APC) and K-Ras increases the size of the CSC population. We previously showed that CPD0857 inactivates Wnt/β-catenin signaling by promoting the ubiquitin-dependent proteasomal degradation of β-catenin and Ras proteins, thereby decreasing proliferation and increasing the apoptosis of CRC lines. CPD0857 also decreased the growth and invasiveness of CRC cells harboring mutant K-Ras resistant to EGFR mAb therapy. Here, we show that CPD0857 treatment decreases proliferation and increases the neuronal differentiation of neural progenitor cells (NPCs). CDP0857 effectively reduced the expression of CSC markers and suppressed self-renewal capacity. CPD0857 treatment also inhibited the proliferation and expression of CSC markers in D-K-Ras MT cells carrying K-Ras, APC and PI3K mutations, indicating the inhibition of PI3K/AKT signaling. Moreover, CPD0857-treated xenograft mice showed a regression of tumor growth and decreased numbers of CSCs in tumors. We conclude that CPD0857 could serve as the basis of a drug development strategy targeting CSCs activated through Wnt/β-catenin-Ras MAPK-PI3K/AKT signaling in CRCs.
    Keywords:  K-Ras; Wnt/β-catenin; cancer stem cell; colorectal cancer; neural progenitor cell
    DOI:  https://doi.org/10.3390/biomedicines10040859
  5. Int J Mol Sci. 2022 Apr 08. pii: 4120. [Epub ahead of print]23(8):
    KRAS: A Druggable Target in Colon Cancer Patients.
    Francesca Negri, Lorena Bottarelli, Gian Luigi de'Angelis, Letizia Gnetti.
      Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific drugs challenging. Indeed, KRAS was considered 'undruggable'. KRASG12C is the most commonly mutated variant of KRAS in non-small cell lung cancer. Currently, the achievements obtained with covalent inhibitors of this variant have given the possibility to assess the best therapeutic approach to KRAS-driven tumors. Mutation-related biochemical assets and the tissue of origin are expected to influence responses to treatment. Further attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising. Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment.
    Keywords:  KRAS oncogene; RAS pathway; adagrasib; colon cancer; sotorasib; targeted therapy
    DOI:  https://doi.org/10.3390/ijms23084120
  6. J Biol Chem. 2022 Apr 13. pii: S0021-9258(22)00356-8. [Epub ahead of print] 101916
    Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK.
    Natasha S Clayton, Millie Fox, Jose J Vicenté-Garcia, Courtney M Schroeder, Trevor D Littlewood, Jonathon I Wilde, Kadalmani Krishnan, Murray J B Brown, Claire Crafter, Helen R Mott, Darerca Owen.
      Activated Cdc42-associated kinase (ACK) is an oncogenic non-receptor tyrosine kinase associated with poor prognosis in several human cancers. ACK promotes proliferation, in part by contributing to the activation of Akt, the major effector of class 1A phosphoinositide 3-kinases (PI3Ks), which transduce signals via membrane phosphoinositol lipids. We now show that ACK also interacts with other key components of class 1A PI3K signaling, the PI3K regulatory subunits. We demonstrate ACK binds to all five PI3K regulatory subunit isoforms and directly phosphorylates p85α, p85β, p50α, and p55α on Tyr607 (or analogous residues). We found that phosphorylation of p85β promotes cell proliferation in HEK293T cells. We demonstrate that ACK interacts with p85α exclusively in nuclear-enriched cell fractions, where p85α phosphorylated at Tyr607 (pTyr607) also resides, and identify an interaction between pTyr607 and the N-terminal SH2 domain that supports dimerization of the regulatory subunits. We infer from this that ACK targets p110-independent p85, and further postulate that these regulatory subunit dimers undertake novel nuclear functions underpinning ACK activity. We conclude that these dimers represent a previously undescribed mode of regulation for the class1A PI3K regulatory subunits and potentially reveal additional avenues for therapeutic intervention.
    Keywords:  Activated Cdc42 kinase; Cdc42; PI3Kinase; cancer; nuclear signalling; p110-independent p85; p85 dimers; protein degradation; protein phosphorylation; tyrosine kinase
    DOI:  https://doi.org/10.1016/j.jbc.2022.101916
  7. Nat Commun. 2022 Apr 19. 13(1): 2057
    Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.
    Kristin M Zimmerman Savill, Brian B Lee, Jason Oeh, Jie Lin, Eva Lin, Wei-Jen Chung, Amy Young, Wennie Chen, Monika Miś, Kathryn Mesh, Jeffrey Eastham, Florian Gnad, Zhaoshi Jiang, Eric W Stawiski, Benjamin Haley, Anneleen Daemen, Xiaojing Wang, Hartmut Koeppen, Zora Modrusan, Scott E Martin, Deepak Sampath, Kui Lin.
      The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.
    DOI:  https://doi.org/10.1038/s41467-022-29655-0
  8. Cancers (Basel). 2022 Apr 12. pii: 1936. [Epub ahead of print]14(8):
    Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors.
    Hossein Taghizadeh, Agnieszka Maj-Hes, Gerald W Prager, Leonhard Müllauer, Robert M Mader.
      In this analysis, we examined the efficacy, feasibility, and limitations of the application of mTOR inhibitors based on the individual molecular profiles of pretreated cancer patients after the failure of all standard treatments in the palliative setting. In this single-center, real-world analysis of our platform for precision medicine, we analyzed the molecular characteristics of 71 cancer patients. The tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite stability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after a consensus discussion. Seventy-one cancer patients with activation of the mTOR pathway were offered an mTORC1-inhibitor-based targeted therapy, and twenty-three (32.4%) of them eventually received the targeted therapy. Only three patients (4.2%) achieved stable disease, of whom one experienced progressive disease again after 9.1 months. The median time to treatment failure was 2.8 months. In total, 110 mutations were detected in 60 patients (84.5%). The three most frequent mutations were found in TP53, PTEN, and KRAS, which accounted for over 50% (56.4%) of all mutations. In sum, in selected patients with heavily pretreated solid tumors with activation of the mTOR pathway, the antitumoral activity of mTORC1 inhibition was weak.
    Keywords:  mTOR; molecular oncology; targeted therapy; tissue-agnostic
    DOI:  https://doi.org/10.3390/cancers14081936
  9. Adv Cancer Res. 2022 ;pii: S0065-230X(22)00002-1. [Epub ahead of print]154 203-226
    PTEN in cancer associated fibroblasts.
    Julia E Lefler, Cara Seward, Michael C Ostrowski.
      Decades of research have concluded that disruptions to Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) have profound effects on cancer progression. However, as our understanding of the tumor stroma has evolved, we can appreciate that disruptions to tumor suppressors such as PTEN should not be studied solely in an epithelial context. Inactivation of PTEN in the stroma is associated with worse outcomes in human cancers, therefore, it is important to understand activities regulated downstream of PTEN in stromal compartments. Studies reviewed herein provide evidence for important mechanistic targets downstream of PTEN signaling in cancer-associated fibroblasts (CAFs), a major component of the tumor stroma. We also discuss the potential clinical implications for these findings.
    Keywords:  Breast cancer; Cancer-associated fibroblasts (CAFs); Extracellular matrix (ECM); PTEN; Pancreatic cancer; Stroma; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/bs.acr.2022.01.002
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