bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
Issue of 2022‒12‒11
thirteen papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research
  1. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.
  2. Mapping the KRAS Proteoform Landscape in Colorectal Cancer Identifies Truncated KRAS4B that Decreases MAPK Signaling.
  3. Recent Advances of PI3 Kinase Inhibitors: Structure Anticancer Activity Relationship Studies.
  4. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.
  5. SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity.
  6. Targeting ferroptosis to treat colorectal cancer.
  7. Development of a multiplex allele-specific qPCR approach for testing PIK3CA mutations in patients with colorectal cancer.
  8. Phosphorylation of PBX2, a novel downstream target of mTORC1, is determined by GSK3 and PP1.
  9. AKTs do not translocate to the nucleus upon stimulation but AKT3 can constitutively signal from the nuclear envelope.
  10. The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC.
  11. Current concepts of anti-EGFR targeting in metastatic colorectal cancer.
  12. Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit.
  13. PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption.
  1. Nat Commun. 2022 Dec 07. 13(1): 7551
    Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.
    Dustin J Flanagan, Raheleh Amirkhah, David F Vincent, Nuray Gundaz, Pauline Gentaz, Patrizia Cammareri, Aoife J McCooey, Amy M B McCorry, Natalie C Fisher, Hayley L Davis, Rachel A Ridgway, Jeroen Lohuis, Joshua D G Leach, Rene Jackstadt, Kathryn Gilroy, Elisa Mariella, Colin Nixon, William Clark, Ann Hedley, Elke K Markert, Douglas Strathdee, Laurent Bartholin, Keara L Redmond, Emma M Kerr, Daniel B Longley, Fiona Ginty, Sanghee Cho, Helen G Coleman, Maurice B Loughrey, Alberto Bardelli, Timothy S Maughan, Andrew D Campbell, Mark Lawler, Simon J Leedham, Simon T Barry, Gareth J Inman, Jacco van Rheenen, Philip D Dunne, Owen J Sansom.
      The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits.
    DOI:  https://doi.org/10.1038/s41467-022-35134-3
  2. J Biol Chem. 2022 Dec 02. pii: S0021-9258(22)01211-X. [Epub ahead of print] 102768
    Mapping the KRAS Proteoform Landscape in Colorectal Cancer Identifies Truncated KRAS4B that Decreases MAPK Signaling.
    Lauren M Adams, Caroline J DeHart, Bryon S Drown, Lissa C Anderson, William Bocik, Emily S Boja, Tara M Hiltke, Christopher L Hendrickson, Henry Rodriguez, Michael Caldwell, Reza Vafabakhsh, Neil L Kelleher.
      The KRAS gene is one of the most frequently mutated oncogenes in human cancer and gives rise to two isoforms, KRAS4A and KRAS4B. KRAS post-translational modifications (PTMs) have the potential to influence downstream signaling. However, the relationship between KRAS PTMs and oncogenic mutations remains unclear, and the extent of isoform-specific modification is unknown. Here, we present the first top-down proteomics study evaluating both KRAS4A and KRAS4B, resulting in 39 completely characterized proteoforms across colorectal cancer cell lines and primary tumor samples. We determined which KRAS PTMs are present, along with their relative abundance, and that proteoforms of KRAS4A versus KRAS4B are differentially modified. Moreover, we identified a subset of KRAS4B proteoforms lacking the C185 residue and associated C-terminal PTMs. By confocal microscopy, we confirmed that this truncated GFP-KRAS4BC185∗ proteoform is unable to associate with the plasma membrane, resulting in a decrease in MAPK signaling pathway activation. Collectively, our study provides a reference set of functionally distinct KRAS proteoforms and the colorectal cancer contexts in which they are present.
    Keywords:  Colorectal cancer; KRAS; MAPK pathway; RAS protein; Top-down proteomics; immunoprecipitation; post-translational modification (PTM); proteoform
    DOI:  https://doi.org/10.1016/j.jbc.2022.102768
  3. Mini Rev Med Chem. 2022 Feb 02.
    Recent Advances of PI3 Kinase Inhibitors: Structure Anticancer Activity Relationship Studies.
    Vivek Asati, Arjun Anant, Debarshi Kar Mahapatra, Sanjay Kumar Bharti.
      Phosphatidyl-inositol-3-kinase (PI3K) has emerged as a potential therapeutic target for the development of novel anticancer drugs. The dysregulation of PI3K has been associated with many human malignancies such as breast, colon, endometrial, brain, and prostate cancers. The PI3K kinases in their different isoforms namely α, β, δ, and γ, encode PIK3CA, PIK3CB, PIK3CD, and PIK3CG genes. Specific gene mutation or overexpression of the protein is responsible for therapeutic failure of current therapeutics. Recently, various PI3K signaling pathway inhibitors have been identified which showed promising therapeutic results by acting on specific isoforms of the kinase too. Several inhibitors containing medicinally privileged scaffolds like oxadiazole, pyrrolotriazine, quinazoline, quinazolinone, quinazoline-chalcone hybrids, quinazoline-sulfonamide, pyrazolochalcone, quinolone hydroxamic acid, benzofuropyridinone, imidazopyridine, benzoxazines, dibenzoxanthene, indoloderivatives, benzimidazole, and benzothiazine derivatives have been developed to target PI3K pathway and/or a specific isoform. The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.
    Keywords:  PI3K; SAR; anticancer agents; kinase; proliferation; signaling pathways
    DOI:  https://doi.org/10.2174/1389450123666220202154757
  4. NPJ Precis Oncol. 2022 Dec 09. 6(1): 91
    Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.
    Jessica K Lee, Smruthy Sivakumar, Alexa B Schrock, Russell Madison, David Fabrizio, Ole Gjoerup, Jeffrey S Ross, Garrett M Frampton, Pavel Napalkov, Meagan Montesion, Jennifer L Schutzman, Xin Ye, Priti S Hegde, Misako Nagasaka, Geoffrey R Oxnard, Ethan S Sokol, Sai-Hong Ignatius Ou, Zhen Shi.
      Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies. Co-alteration landscapes were largely similar across KRAS mutations but distinct from KRAS wild-type, though differences were observed in some tumor types for tumor mutational burden, PD-L1 expression, microsatellite instability, and other mutational signatures. Prognosis of KRAS-mutant versus other genomic cohorts of lung, pancreatic, and colorectal cancer were assessed using a real-world clinicogenomic database. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.
    DOI:  https://doi.org/10.1038/s41698-022-00334-z
  5. Cancer Lett. 2022 Dec 06. pii: S0304-3835(22)00516-X. [Epub ahead of print] 216029
    SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity.
    Wenfang Zheng, Zhiyi Yang, Ping Song, Yingchao Sun, Pan Liu, Lei Yue, Kaiqi Lv, Xinjie Wang, Yuqin Shen, Jianmin Si, Xue Zhang, Yuehai Ke, Hongqiang Cheng, Weiling Hu.
      Despite the promising antitumor activity of RAF/MEK inhibitors for RAS-driven cancers, not all patients respond to these therapies. Adaptive resistance has been reported as a major culprit in non-responders, which can be reversed by SHP2 inhibitors (SHP2is) in multiple cancer cells, however the underlying mechanisms remain unknown. In this study, we found that KRAS-mutant gastric cancer cells respond e to MEK inhibitors (MEKis) with adaptive resistance. Markedly, SHP2 activation accompanied by ERK signaling restoration in MEKi-treated cells, and an MEKi and SHP2i combination had a synergistic effect on downstream signaling blockade. In vivo, SHP099 combined with AZD6244 (selumetinib) was highly efficacious for the treatment of xenografts. Mechanistically, SHP2 was found to interact with the scaffold protein KSR1 through its protein tyrosine phosphatase domain. KSR1 knockdown sensitized cells to AZD6244, whereas a KSR1 activating mutation (S269A) diminished the synergistic anti-proliferative effect of SHP2is and MEKi. Interestingly, activated SHP2, during adaptive resistance to MEKis, impaired the interaction with KSR1, activating KSR1 to promote MAPK signaling. In conclusion, SHP2 promotes adaptive resistance to MEKis by activating KSR1; selumetinib combined with SHP099 might be an available therapeutic strategy for KRAS-mutant gastric cancers.
    Keywords:  KRAS-Mutant gastric cancer; KSR1; MAPK signaling; MEK inhibitor; SHP2
    DOI:  https://doi.org/10.1016/j.canlet.2022.216029
  6. Trends Cell Biol. 2022 Dec 03. pii: S0962-8924(22)00254-9. [Epub ahead of print]
    Targeting ferroptosis to treat colorectal cancer.
    Hong Yan, Ronan Talty, Caroline H Johnson.
      Ferroptosis has emerged as a promising target for colorectal cancer (CRC) treatment. Although disrupting glutathione metabolism is the primary strategy for ferroptosis induction, additional key pathways link ferroptosis to CRC pathogenesis. Here, we discuss arachidonic acid (AA), energy metabolism, AMP-activated protein kinase (AMPK), phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR), and Hippo signaling, summarize key findings, and propose new conceptual avenues for CRC treatment.
    Keywords:  colorectal cancer; ferroptosis; metabolism; therapy
    DOI:  https://doi.org/10.1016/j.tcb.2022.11.003
  7. Heliyon. 2022 Nov;8(11): e11804
    Development of a multiplex allele-specific qPCR approach for testing PIK3CA mutations in patients with colorectal cancer.
    Igor P Oscorbin, Oguljan P Beginyazova, Inna V Khlistun, Darya V Shamovskaya, Natalia A Oskina, Maxim L Filipenko.
      Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases involved in cellular growth and division. Somatic mutations in one of the PI3K catalytic subunit genes, PIK3CA, are frequently found in numerous malignancies, including colorectal cancer (CRC). Several PIK3CA inhibitors are approved for the treatment of breast cancer and lymphoma. Activating mutations in PIK3CA tend to occur in exons 9 and 20, with mutations in other exons 1, 4, and 7 being less common. Most test systems for PIK3CA mutation screening are designed to detect mutations in exons 9 and 20, leaving exons 1-7 overlooked. We have developed a multiplex AS-PCR to screen for PIK3CA mutations in exons 1, 4, 7, 9, and 20. Validation was performed on 515 CRC samples of patients from Siberia and the Far East of Russia. The assay sensitivity was 0.05-0.5% of mutant DNA, and the overall PIK3CA mutation frequency was 13.01%, with 9.32% of mutations in exon 9, 1.94% in exon 20, and 1.74% in exons 1-7. The assay designed is suitable for the analysis of activating PIK3CA mutations in formalin-fixed paraffin-embedded tissue samples. The present work is the first study characterizing the PIK3CA mutation frequency in CRC patients from the eastern part of Russia.
    Keywords:  ARMS; Allele-specific PCR; CRC; Multiplex amplification; PIK3CA; Somatic mutations
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e11804
  8. J Biochem. 2022 Dec 07. pii: mvac094. [Epub ahead of print]
    Phosphorylation of PBX2, a novel downstream target of mTORC1, is determined by GSK3 and PP1.
    Reona Wada, Shun Fujinuma, Hirokazu Nakatsumi, Masaki Matsumoto, Keiichi I Nakayama.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a serine-threonine kinase that is activated by extracellular signals such as nutrients and growth factors. It plays a key role in the control of various biological processes such as protein synthesis and energy metabolism by mediating or regulating the phosphorylation of multiple target molecules, some of which remain to be identified. We have here reanalyzed a large-scale phosphoproteomics data set for mTORC1 target molecules and identified pre-B cell leukemia transcription factor 2 (PBX2) as such a novel target that is dephosphorylated downstream of mTORC1. We confirmed that PBX2, but not other members of the PBX family, is dephosphorylated in an mTORC1 activity-dependent manner. Furthermore, pharmacological and gene knockdown experiments revealed that glycogen synthase kinase 3 (GSK3) and protein phosphatase 1 (PP1) are responsible for the phosphorylation and dephosphorylation of PBX2, respectively. Our results thus suggest that the balance between the antagonistic actions of GSK3 and PP1 determines the phosphorylation status of PBX2 and its regulation by mTORC1.
    Keywords:  glycogen synthase kinase 3 (GSK3); mechanistic target of rapamycin complex 1 (mTORC1); phosphorylation; pre–B cell leukemia transcription factor 2 (PBX2); protein phosphatase 1 (PP1)
    DOI:  https://doi.org/10.1093/jb/mvac094
  9. Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01611-4. [Epub ahead of print]41(10): 111733
    AKTs do not translocate to the nucleus upon stimulation but AKT3 can constitutively signal from the nuclear envelope.
    Ehud Wainstein, Galia Maik-Rachline, John Blenis, Rony Seger.
      AKT is a central signaling protein kinase that plays a role in the regulation of cellular survival metabolism and cell growth, as well as in pathologies such as diabetes and cancer. Human AKT consists of three isoforms (AKT1-3) that may fulfill different functions. Here, we report that distinct subcellular localization of the isoforms directly influences their activity and function. AKT1 is localized primarily in the cytoplasm, AKT2 in the nucleus, and AKT3 in the nucleus or nuclear envelope. None of the isoforms actively translocates into the nucleus upon stimulation. Interestingly, AKT3 at the nuclear envelope is constitutively phosphorylated, enabling a constant phosphorylation of TSC2 at this location. Knockdown of AKT3 induces moderate attenuation of cell proliferation of breast cancer cells. We suggest that in addition to the stimulation-induced activation of the lysosomal/cytoplasmic AKT1-TSC2 pathway, a subpopulation of TSC2 is constitutively inactivated by AKT3 at the nuclear envelope of transformed cells.
    Keywords:  AKT; CP: Cell biology; Tsc2; nuclear envelope; phosphorylation; subcellular localization
    DOI:  https://doi.org/10.1016/j.celrep.2022.111733
  10. Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01642-4. [Epub ahead of print]41(10): 111759
    The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC.
    Ji-Sun Lee, Michael W Lero, Jose Mercado-Matos, Sha Zhu, Minjeong Jo, Claire E Tocheny, Jennifer S Morgan, Leslie M Shaw.
      Despite the strong association of the insulin/insulin-like growth factor (IGF) signaling (IIS) pathway with tumor initiation, recurrence, and metastasis, the mechanism by which this pathway regulates cancer progression is not well understood. Here, we report that IIS supports breast cancer stem cell (CSC) self-renewal in an IRS2-phosphatidylinositol 3-kinase (PI3K)-dependent manner that involves the activation and stabilization of MYC. IRS2-PI3K signaling enhances MYC expression through the inhibition of GSK3β activity and suppression of MYC phosphorylation on threonine 58, thus reducing proteasome-mediated degradation of MYC and sustaining active pS62-MYC function. A stable T58A-Myc mutant rescues CSC function in Irs2-/- cells, supporting the role of this MYC stabilization in IRS2-dependent CSC regulation. These findings establish a mechanistic connection between the IIS pathway and MYC and highlight a role for IRS2-dependent signaling in breast cancer progression.
    Keywords:  CP: Cancer; CSC; IGF; IRS2; MYC; PI3K; breast cancer; cancer stem cell; insulin; insulin receptor substrate; insulin-like growth factor
    DOI:  https://doi.org/10.1016/j.celrep.2022.111759
  11. Front Oncol. 2022 ;12 1048166
    Current concepts of anti-EGFR targeting in metastatic colorectal cancer.
    Bernhard Doleschal, Andreas Petzer, Holger Rumpold.
      Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.
    Keywords:  Metastatic colorectal cancer; clonal evolution; epidermal growth factor receptor; liquid biopsy; maintenance; molecular oncology; systemic treatment
    DOI:  https://doi.org/10.3389/fonc.2022.1048166
  12. Front Oncol. 2022 ;12 1004669
    Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit.
    Wenjuan Ning, Thomas M Marti, Patrick Dorn, Ren-Wang Peng.
      Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRASG12C inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRASG12C, such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRASG12C inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRASG12C-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRASG12C inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT.
    Keywords:  EMT; KRAS G12C inhibitors; TME; non-genetic adaptive resistance; symbiosis
    DOI:  https://doi.org/10.3389/fonc.2022.1004669
  13. Sci Adv. 2022 Dec 09. 8(49): eade7823
    PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption.
    Sophia Ladraa, Lola Zerbib, Charles Bayard, Antoine Fraissenon, Quitterie Venot, Gabriel Morin, Alexandre P Garneau, Pierre Isnard, Célia Chapelle, Clément Hoguin, Sylvie Fraitag, Jean-Paul Duong, Laurent Guibaud, Alix Besançon, Sophie Kaltenbach, Patrick Villarese, Vahid Asnafi, Christine Broissand, Nicolas Goudin, Michael Dussiot, Ivan Nemazanyy, Thomas Viel, Gwennhael Autret, Céline Cruciani-Guglielmacci, Jessica Denom, Julie Bruneau, Bertrand Tavitian, Christophe Legendre, Julien Dairou, Jean-Marc Lacorte, Pacifique Levy, Mario Pende, Michel Polak, Guillaume Canaud.
      PIK3CA-related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA. Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA-related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA-adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.
    DOI:  https://doi.org/10.1126/sciadv.ade7823
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