bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2022–05–01
eight papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research
  1. Clinicopathological Significance of PTEN Expression and Its Prognostic Effect in Colorectal Adenocarcinoma Patients.
  2. Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer.
  3. At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy.
  4. Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report.
  5. The synergistic anti-colon cancer effect of Aurora A inhibitors and AKT inhibitors through PI3K/AKT pathway.
  6. A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer.
  7. Systematic discovery and validation of T cell targets directed against oncogenic KRAS mutations.
  8. Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
  1. Iran J Pathol. 2022 ;17(2): 150-158
    Clinicopathological Significance of PTEN Expression and Its Prognostic Effect in Colorectal Adenocarcinoma Patients.
    Zohreh Mirzapour Abbas Abadi, Fatemeh Samiee Rad, Dariush Hamedi Asl, Babak Rahmani, Mahmood Soleimani Dodaran, Amir Peimani.
       Background & Objective: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located at chromosome 10. PTEN is a regulator of the PI3K/AKT signaling pathway that inhibits cell proliferation and promotes apoptosis. PTEN loss of function occurs in a spectrum of cancers, including colorectal adenocarcinoma. This study aimed to investigate the probable correlation of negative PTEN expression with clinicopathological features and colorectal adenocarcinoma (CRC) patients' survival.
    Methods: In this cross-sectional study using Immunohistochemistry stainingPTEN expression status on 151 CRC tissues was evaluated. Then the results of IHC staining was compared to those of clinicopathological features. The relationship between PTEN and KRAS mutation status was also investigated.
    Results: Of 151 CRC samples, 89 (58.9%) were negative for PTEN expression. Loss of PTEN expression was associated with KRAS mutation (P<0.0001), lymph node metastasis (P=0.002), and advanced tumor stage (P=0.016), whereas no significant association was found with other clinicopathological features. Multivariate analysis indicated that tumor site and KRAS mutation were independent prognostic CRC patients (P<0.05). The Kaplan-Meier analysis indicated a correlation between loss of PTEN expression and overall survival of patients with colorectal adenocarcinoma (P= 0.01).
    Conclusion: The current study suggests that decreasing PTEN expression or its negative expression may be associated with a higher stage and poor prognosis. Combined analysis of mutated KRAS and PTEN expression could be a good predictor of disease prognosis as well as its clinical outcomes.
    Keywords:  Adenocarcinoma; Clinicopathology; Colorectal cancer; PTEN; Prognostic factors
    DOI:  https://doi.org/10.30699/IJP.2021.531779.2653
  2. Oncologist. 2022 Apr 26. pii: oyac077. [Epub ahead of print]
    Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer.
    Marwan Fakih, Huakang Tu, Hil Hsu, Shivani Aggarwal, Emily Chan, Marko Rehn, Victoria Chia, Scott Kopetz.
       BACKGROUND: The KRAS p.G12C mutation has recently become an actionable drug target. To further understand KRAS p.G12C disease, we describe clinicopathologic characteristics, treatment patterns, overall survival (OS), and real-world progression-free survival (rwPFS) in patients with metastatic colorectal cancer (mCRC), KRAS p.G12C mutations (KRAS G12C), and other KRAS mutations (KRAS non-G12C) using a de-identified database.
    PATIENTS AND METHODS: Clinical and tumor characteristics, including treatments received, genomic profile, and clinical outcomes were assessed for patients from a US clinical genomic database with mCRC diagnosed between January 1, 2011, and March 31, 2020, with genomic sequencing data available.
    RESULTS: Of 6477 patients with mCRC (mCRC cohort), 238 (3.7%) had KRAS G12C and 2947 (45.5%) had KRAS non-G12C mutations. Treatment patterns were generally comparable across lines of therapy (LOT) in KRAS G12C versus KRAS non-G12C cohorts. Median (95% CI) OS after the first LOT was 16.1 (13.0-19.0) months for the KRAS G12C cohort versus 18.3 (17.2-19.3) months for the KRAS non-G12C cohort, and 19.2 (18.5-19.8) months for the mCRC overall cohort; median (95% CI) rwPFS was 7.4 (6.3-9.5), 9.0 (8.2-9.7), and 9.2 (8.6-9.7) months, respectively. The different KRAS non-G12C mutations examined did not affect clinical outcomes. Median OS and rwPFS for all cohorts declined with each subsequent LOT.
    CONCLUSIONS: Patients with KRAS p.G12C-mutant mCRC have poor treatment outcomes, and outcomes appear numerically worse than for those without this mutation, indicating potential prognostic implications for KRAS p.G12C mutations and an unmet medical need in this population.
    Keywords:   KRAS p.G12C; metastatic colorectal cancer; retrospective
    DOI:  https://doi.org/10.1093/oncolo/oyac077
  3. Nat Rev Clin Oncol. 2022 Apr 28.
    At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy.
    Neil Vasan, Lewis C Cantley.
      Numerous agents targeting various phosphatidylinositol 3-kinase (PI3K) pathway components, including PI3K, AKT and mTOR, have been tested in oncology clinical trials, resulting in regulatory approvals for the treatment of selected patients with breast cancer, certain other solid tumours or particular haematological malignancies. However, given the prominence of PI3K signalling in cancer and the crucial role of this pathway in linking cancer growth with metabolism, these clinical results could arguably be improved upon. In this Review, we discuss past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, as well as identification and abrogation of signalling-related and metabolic mechanisms of resistance, and interventions to improve management of prohibitive adverse events. We highlight the advantages and limitations of laboratory-based model systems used to study the PI3K pathway, and propose technologies and experimental inquiries to guide the future clinical deployment of PI3K pathway inhibitors in the treatment of cancer.
    DOI:  https://doi.org/10.1038/s41571-022-00633-1
  4. Front Oncol. 2022 ;12 863639
    Concurrent RAS and RAS/BRAF V600E Variants in Colorectal Cancer: More Frequent Than Expected? A Case Report.
    Veronica Zelli, Alessandro Parisi, Leonardo Patruno, Katia Cannita, Corrado Ficorella, Carla Luzi, Chiara Compagnoni, Francesca Zazzeroni, Edoardo Alesse, Alessandra Tessitore.
      The assessment of RAS and BRAF mutational status is one of the main steps in the diagnostic and therapeutic algorithm of metastatic colorectal cancer (mCRC). Multiple mutations in the BRAF and RAS pathway are described as a rare event, with concurrent variants in KRAS and BRAF genes observed in approximately 0.05% of mCRC cases. Here, we report data from a case series affected by high-risk stage III and stage IV CRC and tested for RAS and BRAF mutation, treated at our Medical Oncology Unit. The analysis of KRAS, NRAS (codons 12, 13, 59, 61, 117, 146), and BRAF (codon 600) hotspot variants was performed in 161 CRC tumors from August 2018 to September 2021 and revealed three (1.8%) patients showing mutations in both KRAS and BRAF (V600E), including two cases with earlier CRC and one with metastatic disease. We also identified one patient (0.6%) with a mutation in both KRAS and NRAS genes and another one (0.6%) with a double KRAS mutation. Notably, the latter was characterized by aggressive behavior and poor clinical outcome. The mutational status, pathological features, and clinical history of these five CRC cases are described. Overall, this study case series adds evidence to the limited available literature concerning both the epidemiological and clinical aspects of CRC cases characterized by the presence of concurrent RAS/BRAF variants. Future multicentric studies will be required to increase the sample size and provide additional value to results observed so far in order to improve clinical management of this subgroup of CRC patients.
    Keywords:  case report; clinical–pathological features; colorectal cancer; concurrent RAS/BRAF variants; mutation frequency
    DOI:  https://doi.org/10.3389/fonc.2022.863639
  5. Anticancer Agents Med Chem. 2022 Apr 22.
    The synergistic anti-colon cancer effect of Aurora A inhibitors and AKT inhibitors through PI3K/AKT pathway.
    Cheng Sun, Zhen Qu, Weilin Liu, Zhigang Qiu, Yanfeng Lü, Zhenqing Sun.
       BACKGROUND: Both AKT and Aurora inhibitors are a potential therapeutic agent for the treatment of malignant tumors. However, the role of combined inhibition of AKT and Aurora in colon cancer and its underlying mechanism have yet to be fully investigated.
    OBJECTIVE: To investigate the role of combined AKT and Aurora inhibitors in colon cancer and its underlying mechanisms.
    METHODS: CCK8 assay, colony formation assay, and flow cytometry were performed to analyze the proliferation and apoptosis of colon cancer cell line SW480 treated with combined AKT inhibitor MK2206 and Aurora inhibitor Alisertib, respectively. And tumor formation and growth were measured in tumor allograft model mice administered with the combined inhibitors. Western blot analysis was used to examine the expression levels of apoptosis-related proteins and signal transduction pathway components. The PI3K agonist 740Y-P and Overexpression of AKT are used to verify whether the PI3K/AKT pathway plays an anti-tumor effect when combined with inhibitory administration.
    RESULTS: Aurora A inhibitor Alisertib and AKT inhibitor MK2206 displayed consistent and synergistic antiproliferation and proapoptotic effects. Combined inhibition of Aurora A and AKT down-regulated the expression of Bcl-2/Bax and up-regulated the expression of cleaved-caspase-3 and cleaved-PARP. While single-drug treatment can significantly inhibit the expression of P-PI3K and P-AKT as well as increasing the expression of P53 and H2A.X, the combined drugs had a more significant inhibitory effect than the single drug. Moreover, administration of PI3K agonist 740Y-P and AKT1 overexpression experiments proved that the combined drugs exert an anticancer effect by inhibiting the PI3K/AKT pathway. Meanwhile, we showed that the combined administration had an anti-colon cancer effect on tumor allograft mice, and the underlying mechanism involved inhibition of the PI3K/AKT pathway.
    CONCLUSION: Combined administration of Aurora A inhibitor Alisertib and AKT inhibitor MK2206 can inhibit the proliferation of colon cancer cells and induce apoptosis, while inhibiting tumor growth in vivo. The underlying mechanism may involve the PI3K/AKT pathway and DNA damage pathway.
    Keywords:  Apoptosis; Aurora kinase A; Colon cancer; P53; PI3K/Akt; Proliferation
    DOI:  https://doi.org/10.2174/1871520622666220422133537
  6. Sci Adv. 2022 Apr 29. 8(17): eabm3108
    A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer.
    Helen Tanton, Tomasz Sewastianik, Hyuk-Soo Seo, David Remillard, Roodolph St Pierre, Pratyusha Bala, Daulet Aitymbayev, Peter Dennis, Keith Adler, Ezekiel Geffken, Zoe Yeoh, Nicholas Vangos, Filip Garbicz, David Scott, Nilay Sethi, James Bradner, Sirano Dhe-Paganon, Ruben D Carrasco.
      Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.
    DOI:  https://doi.org/10.1126/sciadv.abm3108
  7. Cell Rep Methods. 2021 Sep 27. 1(5): 100084
    Systematic discovery and validation of T cell targets directed against oncogenic KRAS mutations.
    Jaewon Choi, Scott P Goulding, Brandon P Conn, Christopher D McGann, Jared L Dietze, Jessica Kohler, Divya Lenkala, Antoine Boudot, Daniel A Rothenberg, Paul J Turcott, John R Srouji, Kendra C Foley, Michael S Rooney, Marit M van Buuren, Richard B Gaynor, Jennifer G Abelin, Terri A Addona, Vikram R Juneja.
      Oncogenic mutations in KRAS can be recognized by T cells on specific class I human leukocyte antigen (HLA-I) molecules, leading to tumor control. To date, the discovery of T cell targets from KRAS mutations has relied on occasional T cell responses in patient samples or the use of transgenic mice. To overcome these limitations, we have developed a systematic target discovery and validation pipeline. We evaluate the presentation of mutant KRAS peptides on individual HLA-I molecules using targeted mass spectrometry and identify 13 unpublished KRASG12C/D/R/V mutation/HLA-I pairs and nine previously described pairs. We assess immunogenicity, generating T cell responses to nearly all targets. Using cytotoxicity assays, we demonstrate that KRAS-specific T cells and T cell receptors specifically recognize endogenous KRAS mutations. The discovery and validation of T cell targets from KRAS mutations demonstrate the potential for this pipeline to aid the development of immunotherapies for important cancer targets.
    Keywords:  HLA; PRM; RAS; T cell; TCR; cancer; immunotherapy; mass spectrometry; neoantigen
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100084
  8. Nat Med. 2022 Apr 28.
    Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
    Smita S Chandran, Jiaqi Ma, Martin G Klatt, Friederike Dündar, Chaitanya Bandlamudi, Pedram Razavi, Hannah Y Wen, Britta Weigelt, Paul Zumbo, Si Ning Fu, Lauren B Banks, Fei Yi, Enric Vercher, Inaki Etxeberria, Watchain D Bestman, Arnaud Da Cruz Paula, Ilinca S Aricescu, Alexander Drilon, Doron Betel, David A Scheinberg, Brian M Baker, Christopher A Klebanoff.
      Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively 'featureless' surface dominated by the peptide's backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.
    DOI:  https://doi.org/10.1038/s41591-022-01786-3
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