bims-pimaco 2023-01-08 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–01–08
seven papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Genetic heterogeneity and tissue-specific patterns of tumors with multiple PIK3CA mutations.
Dynamic regulation of RAS and RAS signaling.
mTORC2: a multifaceted regulator of autophagy.
RAS nanoclusters are cell surface transducers that convert extracellular stimuli to intracellular signaling.
Whole-genome CRISPR screening identifies PI3K/AKT as a downstream component of the oncogenic GNAQ-Focal Adhesion Kinase signaling circuitry.
An immunocompetent rectal cancer model to study radiation therapy.
Function-oriented synthesis of Imidazo[1,2-a]pyrazine and Imidazo[1,2-b]pyridazine derivatives as potent PI3K/mTOR dual inhibitors.

Clin Cancer Res. 2023 Jan 03. pii: CCR-22-2270. [Epub ahead of print]

Genetic heterogeneity and tissue-specific patterns of tumors with multiple PIK3CA mutations.

Smruthy Sivakumar, Dexter X Jin, Ruchita Rathod, Jeffrey Ross, Lewis C Cantley, Maurizio Scaltriti, Jessica W Chen, Katherine E Hutchinson, Timothy R Wilson, Ethan S Sokol, Neil Vasan.

PURPOSE: To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes.
EXPERIMENTAL DESIGN: We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response.
RESULTS: Multi-PIK3CA mutations are found in 11% of all PIK3CA-mutant tumors, including 9% of low tumor mutational burden PIK3CA-mutant tumors, and are enriched in breast and gynecologic cancers. Multi-PIK3CA mutations are frequently clonal and in cis on the same allele and occur at characteristic positions across tumor types. These mutations tend to be mutually exclusive of mutations in other driver genes, and of genes in the PI3K pathway. Among PIK3CA-mutant tumors with a high TMB, 18% are multi-PIK3CA mutant and often harbor an APOBEC mutational signature. Despite large differences in specific allele combinations comprising multi-PIK3CA mutant tumors, especially across cancer types, patients with different classes of multi-PIK3CA mutant ER+ HER2- breast cancers respond similarly to PI3K inhibition.
CONCLUSIONS: Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2270
Biochem J. 2023 Jan 13. 480(1): 1-23

Dynamic regulation of RAS and RAS signaling.

Walter Kolch, Dénes Berta, Edina Rosta.

  RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.

Keywords:  RAS proteins; biological networks; cancer; dynamics; signaling

DOI:  https://doi.org/10.1042/BCJ20220234
Cell Commun Signal. 2023 Jan 05. 21(1): 4

mTORC2: a multifaceted regulator of autophagy.

Yanan Sun, Huihui Wang, Taiqi Qu, Junjie Luo, Peng An, Fazheng Ren, Yongting Luo, Yixuan Li.

  Autophagy is a multi-step catabolic process that delivers cellular components to lysosomes for degradation and recycling. The dysregulation of this precisely controlled process disrupts cellular homeostasis and leads to many pathophysiological conditions. The mechanistic target of rapamycin (mTOR) is a central nutrient sensor that integrates growth signals with anabolism to fulfil biosynthetic and bioenergetic requirements. mTOR nucleates two distinct evolutionarily conserved complexes (mTORC1 and mTORC2). However, only mTORC1 is acutely inhibited by rapamycin. Consequently, mTORC1 is a well characterized regulator of autophagy. While less is known about mTORC2, the availability of acute small molecule inhibitors and multiple genetic models has led to increased understanding about the role of mTORC2 in autophagy. Emerging evidence suggests that the regulation of mTORC2 in autophagy is mainly through its downstream effector proteins, and is variable under different conditions and cellular contexts. Here, we review recent advances that describe a role for mTORC2 in this catabolic process, and propose that mTORC2 could be a potential clinical target for the treatment of autophagy-related diseases. Video abstract.

Keywords:  AKT; Autophagy; PKC; SGK-1; mTORC2

DOI:  https://doi.org/10.1186/s12964-022-00859-7
FEBS Lett. 2023 Jan 03.

RAS nanoclusters are cell surface transducers that convert extracellular stimuli to intracellular signaling.

Yong Zhou, John F Hancock.

  Mutations of RAS oncogenes (HRAS, KRAS and NRAS) can contribute to the development of cancers and genetic disorders (RASopathies). The spatiotemporal organization of RAS is an important property that warrants further investigation. In order to function, wild-type or oncogenic mutants of RAS must be localized to the inner leaflet of the plasma membrane (PM), which is driven by interactions between their C-terminal membrane-anchoring domains and PM lipids. The isoform-specific RAS-lipid interactions promote the formation of nanoclusters on the PM. As main sites for effector recruitment, these nanoclusters are biologically important. Since the spatial distribution of lipids is sensitive to changing environments, such as mechanical and electrical perturbations, RAS nanoclusters act as transducers to convert external stimuli to intracellular mitogenic signaling. As such, effective inhibition of RAS oncogenesis requires consideration of the complex interplay between RAS nanoclusters and various cell surface and extracellular stimuli. In this Review, we discuss in detail how, by sorting specific lipids in the PM, RAS nanoclusters act as transducers to convert external stimuli into intracellular signaling.

Keywords:  RAS small GTPases; electron microscopy; membrane curvature; nanoclusters; phosphatidylserine; plasma membrane

DOI:  https://doi.org/10.1002/1873-3468.14569
J Biol Chem. 2022 Dec 31. pii: S0021-9258(22)01309-6. [Epub ahead of print] 102866

Whole-genome CRISPR screening identifies PI3K/AKT as a downstream component of the oncogenic GNAQ-Focal Adhesion Kinase signaling circuitry.

Nadia Arang, Simone Lubrano, Damiano Cosimo Rigiracciolo, Daniela Nachmanson, Scott M Lippman, Prashant Mali, Olivier Harismendy, J Silvio Gutkind.

G proteins and G protein-coupled receptors (GPCRs) activate a diverse array of signal transduction pathways that promote cell growth and survival. Indeed, hotspot activating mutations in GNAQ/GNA11, encoding Gαq proteins, are known to be driver oncogenes in uveal melanoma (UM), for which there are limited effective therapies currently available. Focal Adhesion Kinase (FAK) has been recently shown to be a central mediator of Gαq-driven signaling in UM, and as a result, is being explored clinically as a therapeutic target for UM, both alone and in combination therapies. Despite this, the repertoire of Gαq/FAK-regulated signaling mechanisms have not been fully elucidated. Here, we used a whole-genome CRISPR screen in GNAQ-mutant UM cells to identify mechanisms that, when overactivated, lead to reduced sensitivity to FAK inhibition. In this way, we found the PI3K/AKT signaling pathway represented a major resistance driver. Our dissection of the underlying mechanisms revealed that Gαq promotes PI3K/AKT activation via a conserved signaling circuitry mediated by FAK. Further analysis demonstrated that FAK activates PI3K through the association and tyrosine phosphorylation of the p85 regulatory subunit of PI3K, and that UM cells require PI3K/AKT signaling for survival. These findings establish a novel link between Gαq-driven signaling and the stimulation of PI3K, as well as demonstrate aberrant activation of signaling networks underlying the growth and survival of UM and other Gαq-driven malignancies.

DOI: https://doi.org/10.1016/j.jbc.2022.102866
Cell Rep Methods. 2022 Dec 19. 2(12): 100353

An immunocompetent rectal cancer model to study radiation therapy.

Jin K Kim, Chao Wu, Michael Del Latto, Yajing Gao, Seo-Hyun Choi, Maria Kierstead, Charles-Etienne Gabriel Sauvé, Canan Firat, Almudena Chaves Perez, Jussi Sillanpaa, Chin-Tung Chen, Kayla E Lawrence, Philip B Paty, Francisco M Barriga, John E Wilkinson, Jinru Shia, Charles L Sawyers, Scott W Lowe, Julio García-Aguilar, Paul B Romesser, J Joshua Smith.

  We describe a mouse model of rectal cancer (RC) involving rapid tumor organoid engraftment via orthotopic transplantation in an immunocompetent setting. This approach uses simple mechanical disruption to allow engraftment, avoiding the use of dextran sulfate sodium. The resulting RC tumors invaded from the mucosal surface and metastasized to distant organs. Histologically, the tumors closely resemble human RC and mirror remodeling of the tumor microenvironment in response to radiation. This murine RC model thus recapitulates key aspects of human RC pathogenesis and presents an accessible approach for more physiologically accurate, preclinical efficacy studies.

Keywords:  immunocompetent mouse model; radiation; rectal cancer; tumor microenvironment; tumor organoids

DOI:  https://doi.org/10.1016/j.crmeth.2022.100353
Eur J Med Chem. 2022 Dec 20. pii: S0223-5234(22)00932-1. [Epub ahead of print]247 115030

Function-oriented synthesis of Imidazo[1,2-a]pyrazine and Imidazo[1,2-b]pyridazine derivatives as potent PI3K/mTOR dual inhibitors.

Chuchu Li, Yuqiao Han, Zhengyang Wang, Yanan Yu, Chen Wang, Ziwei Ren, Yanzhi Guo, Tong Zhu, XuWen Li, Suzhen Dong, Mingliang Ma.

  The PI3K-Akt-mTOR signaling pathway is a highly frequently activated signal transduction pathway in human malignancies, which has been a hot target for anti-tumoral drug discovery. Based on our previous research, a function-oriented synthesis (FOS) of imidazo[1,2-a]pyrazines and imidazo[1,2-b]pyridazines was conducted, and their anticancer activities in vitro and in vivo were evaluated. Among them, compound 42 exhibited excellent dual PI3K/mTOR inhibitory activity, with IC50 values on PI3Kα and mTOR of 0.06 nM and 3.12 nM, respectively, much better than our previous reported compound 15a. Furthermore, compound 42 exhibited significant in vitro and in vivo anti-tumoral activities, great kinase selectivity, low hepatotoxicity, modest plasma clearance and acceptable oral bioavailability, which is a promising PI3K/mTOR targeted anti-cancer drug candidate.

Keywords:  Antitumor activity; Cancer; Hepatotoxicity; PI3K/mTOR dual inhibitors

DOI:  https://doi.org/10.1016/j.ejmech.2022.115030