bims-pimaco 2023-05-21 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–05–21
seven papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer.
The 'New (Nu)-clear' evidence for the tumor-driving role of PI3K.
The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers.
Mechanisms controlling membrane recruitment and activation of autoinhibited SHIP1.
Targeted hyperactivation of AKT through inhibition of ectopic expressed SHIP1 induces cell death in colon carcinoma cells and derived metastases.
Cancer resistance via the downregulation of the tumor suppressors RKIP and PTEN expressions: therapeutic implications.
Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies.

Cancer Res. 2023 May 17. pii: CAN-22-3032. [Epub ahead of print]

The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer.

Sahar Mafi, Elham Ahmadi, Eileen Meehan, Conner Chiari, Behzad Mansoori, Hossein Sadeghi, Sahar Milani, Morteza Jafarinia, Shahram Taeb, Bayan Mafakheri Bashmagh, Seyed Mohammad Ali Mansoorian, Mohammad Sadegh Soltani-Zangbar, Kepeng Wang, Davoud Rostamzadeh.

The mTOR complex 1 (mTORC1) coordinates several important environmental and intracellular cues to control a variety of biological processes, such as cell growth, survival, autophagy, and metabolism in response to energy levels, growth signals, and nutrients. The endoplasmic reticulum (ER) is a crucial intracellular organelle that is essential for numerous cellular functions, including the synthesis, folding and modification of newly synthesized proteins, stress responsiveness, and maintainence of cellular homeostasis. mTOR-mediated upregulation of protein synthesis induces the accumulation of misfolded or unfolded proteins in the ER lumen which induces ER stress, leading to activation of the unfolded protein response (UPR) pathway. Reciprocally, ER stress regulates the PI3K/AKT/mTOR signaling pathway. Therefore, under pathological conditions, the crosstalk between the mTOR and UPR signaling pathways during cellular stress can critically affect cancer cell fate and may be involved in the pathogenesis and therapeutic outcome of cancer. Here, we discuss accumulating evidence showing the mechanism of action, interconnections, and molecular links between mTOR signaling and ER stress in tumorigenesis and highlight potential therapeutic implications for numerous cancers.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3032
Acta Mater Med. 2022 ;1(2): 193-196

The 'New (Nu)-clear' evidence for the tumor-driving role of PI3K.

Franklin Mayca Pozo, Tony Hunter, Youwei Zhang.

  The classical phosphatidylinositol 3-kinases (PI3Ks) are heterodimers of p110 and p85. PIK3CA, the gene encoding the catalytic p110α subunit, is one of the most frequently mutated oncogenes in human cancers with hot spot mutations occurring in the helical domain or in the kinase domain. Tumors with these two types of PIK3CA mutations show overlapping yet distinct phenotypes; however, the underlying mechanisms remain unclear. In a recent publication [1], Hao et al revealed exciting findings about the PI3K p85β regulatory subunit in promoting PIK3CA helical domain mutation-driven cancer progression. The authors found that p85β disassociated from the PI3K complex and translocated into the nucleus only in cancer cells harboring PIK3CA helical domain mutations. Disrupting nuclear localization of p85β suppressed mouse tumor growth of cancer cells with PIK3CA helical domain mutation. Mechanistically, they elegantly showed that nuclear p85β recruited the deubiquitinase USP7 to stabilize the histone methyltransferases EZH1/2, leading to enhanced H3K27 trimethylation and gene transcription. Combining an EZH inhibitor with a PI3K inhibitor specifically resulted in regression of mouse xenograft tumors with PIK3CA helical domain mutations. These findings illustrate a previously uncharacterized function of p85β in tumor development and suggest an effective approach to target tumors with PIK3CA helical mutations.

Keywords:  PI3K; cancer mutation; colorectal cancer; nuclear translocation; p110; p85

DOI:  https://doi.org/10.15212/amm-2022-0013
Cancers (Basel). 2023 Apr 19. pii: 2375. [Epub ahead of print]15(8):

The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers.

Simon Manuel Tria, Matthew E Burge, Vicki L J Whitehall.

  Colorectal cancer is one of the world's most prevalent and lethal cancers. Mutations of the KRAS gene occur in ~40% of metastatic colorectal cancers. While this cohort has historically been difficult to manage, the last few years have shown exponential growth in the development of selective inhibitors targeting KRAS mutations. Their foremost mechanism of action utilizes the Switch II binding pocket and Cys12 residue of GDP-bound KRAS proteins in G12C mutants, confining them to their inactive state. Sotorasib and Adagrasib, both FDA-approved for the treatment of non-small cell lung cancer (NSCLC), have been pivotal in paving the way for KRAS G12C inhibitors in the clinical setting. Other KRAS inhibitors in development include a multi-targeting KRAS-mutant drug and a G12D mutant drug. Treatment resistance remains an issue with combination treatment regimens including indirect pathway inhibition and immunotherapy providing possible ways to combat this. While KRAS-mutant selective therapy has come a long way, more work is required to make this an effective and viable option for patients with colorectal cancer.

Keywords:  GTPase-activating protein (GAP); Kirsten rat sarcoma virus (KRAS); guanine diphosphate (GDP); guanine nucleotide exchange factor (GEF); guanine triphosphate (GTP); mitogen-activated pathway kinase (MAPK)

DOI:  https://doi.org/10.3390/cancers15082375
bioRxiv. 2023 May 01. pii: 2023.04.30.538895. [Epub ahead of print]

Mechanisms controlling membrane recruitment and activation of autoinhibited SHIP1.

Grace L Waddell, Emma E Drew, Henry P Rupp, Scott D Hansen.

Signal transduction downstream of growth factor and immune receptor activation relies on the production of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P 3 ) lipids by phosphoinositide-3-kinase (PI3K). Regulating the strength and duration of PI3K signaling in immune cells, Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) controls the dephosphorylation of PI(3,4,5)P 3 to generate PI(3,4)P 2 . Although SHIP1 has been shown to regulate neutrophil chemotaxis, B-cell signaling, and cortical oscillations in mast cells, the role that lipid and protein interactions serve in controlling SHIP1 membrane recruitment and activity remains unclear. Using single molecule TIRF microscopy, we directly visualized membrane recruitment and activation of SHIP1 on supported lipid bilayers and the cellular plasma membrane. We find that SHIP1's interactions with lipids are insensitive to dynamic changes in PI(3,4,5)P 3 both in vitro and in vivo. Very transient SHIP1 membrane interactions were detected only when membranes contained a combination of phosphatidylserine (PS) and PI(3,4,5)P 3 lipids. Molecular dissection reveals that SHIP1 is autoinhibited with the N-terminal SH2 domain playing a critical role in suppressing phosphatase activity. Robust SHIP1 membrane localization and relief of autoinhibition can be achieved through interactions with immunoreceptor derived phosphopeptides presented either in solution or conjugated to supported membranes. Overall, this work provides new mechanistic details concerning the dynamic interplay between lipid binding specificity, protein-protein interactions, and activation of autoinhibited SHIP1.

DOI: https://doi.org/10.1101/2023.04.30.538895
Cell Signal. 2023 May 17. pii: S0898-6568(23)00134-1. [Epub ahead of print] 110720

Targeted hyperactivation of AKT through inhibition of ectopic expressed SHIP1 induces cell death in colon carcinoma cells and derived metastases.

Patrick A H Ehm, Michael Linnebacher, Andreas Block, Christoph Rehbach, Manfred Jücker.

  Current therapeutic approaches for colorectal cancer (CRC) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the PI3K/AKT-signaling may lead to trigger CRC cell death. Recently we found that hematopoietic SHIP1 is ectopically expressed in CRC cells. Here we show that SHIP1 is more strongly expressed in metastatic cells than in the primary cancer cells, which allows for an increase in AKT signaling in metastatic cells, giving them an advantage from an evolutionary point of view. Mechanistically, the increased SHIP1 expression reduces the activation of the PI3K/ AKT signaling to a value that is below the threshold that leads to cell death. This mechanism gives the cell a selection advantage. We show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SHIP1, induces acute cell death in CRC cells, because of excessive accumulation of reactive oxygen species. Our results demonstrate that CRC cells critically depend on mechanisms to fine-tune PI3K/AKT activity and show SHIP1 inhibition as an unexpectedly promising concept for CRC therapy.

Keywords:  Colorectal cancer; Inositol 5-phosphatase; Metastasis; PI3K/AKT-signaling; ROS; SHIP1; Targeted hyperactivation

DOI:  https://doi.org/10.1016/j.cellsig.2023.110720
Explor Target Antitumor Ther. 2023 ;4(2): 170-207

Cancer resistance via the downregulation of the tumor suppressors RKIP and PTEN expressions: therapeutic implications.

Matthew Moghaddam, Silvia Vivarelli, Luca Falzone, Massimo Libra, Benjamin Bonavida.

  The Raf kinase inhibitor protein (RKIP) has been reported to be underexpressed in many cancers and plays a role in the regulation of tumor cells' survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, is either mutated, underexpressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. The transcriptional and posttranscriptional regulations of RKIP and PTEN expressions and their roles in resistance were reviewed. The underlying mechanism of the interrelationship between the signaling expressions of RKIP and PTEN in cancer is not clear. Several pathways are regulated by RKIP and PTEN and the transcriptional and post-transcriptional regulations of RKIP and PTEN is significantly altered in cancers. In addition, RKIP and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In addition, molecular and bioinformatic data revealed crosstalk signaling networks that regulate the expressions of both RKIP and PTEN. These crosstalks involved the mitogen-activated protein kinase (MAPK)/PI3K pathways and the dysregulated nuclear factor-kappaB (NF-κB)/Snail/Yin Yang 1 (YY1)/RKIP/PTEN loop in many cancers. Furthermore, further bioinformatic analyses were performed to investigate the correlations (positive or negative) and the prognostic significance of the expressions of RKIP or PTEN in 31 different human cancers. These analyses were not uniform and only revealed that there was a positive correlation between the expression of RKIP and PTEN only in few cancers. These findings demonstrated the existence of signaling cross-talks between RKIP and PTEN and both regulate resistance. Targeting either RKIP or PTEN (alone or in combination with other therapies) may be sufficient to therapeutically inhibit tumor growth and reverse the tumor resistance to cytotoxic therapies.

Keywords:  PTEN; RKIP; bioinformatics; cross-talks; resistance; signaling

DOI:  https://doi.org/10.37349/etat.2023.00128
Cancers (Basel). 2023 Apr 13. pii: 2279. [Epub ahead of print]15(8):

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies.

Claire Breal, Frederic Beuvon, Thibault de Witasse-Thezy, Solene Dermine, Patricia Franchi-Rezgui, Benedicte Deau-Fisher, Lise Willems, Eric Grignano, Adrien Contejean, Didier Bouscary, Jean Luc Faillie, Jean-Marc Treluyer, Corinne Guerin, Laurent Chouchana, Marguerite Vignon.

  The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Keywords:  adverse drug reaction; colitis; idelalisib; pharmacovigilance; phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor

DOI:  https://doi.org/10.3390/cancers15082279