bims-pimaco 2023-11-05 papers

bims-pimaco

Biomed News

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023‒11‒05
seven papers selected by
Lucas B. Zeiger, Beatson Institute for Cancer Research

Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations.
A New Wave of PI3Kα Inhibitors.
Cholesterol regulates insulin-induced mTORC1 signaling.
TAS0612, a novel RSK, AKT, and S6K inhibitor, exhibits antitumor effects in preclinical tumor models.
Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1.
Review: The PI3K-AKT-mTOR signal transduction pathway in canine cancer.
Discovery and clinical proof-of-concept of RLY-2608, a first-in-class mutant-selective allosteric PI3Ka inhibitor that decouples anti-tumor activity from hyperinsulinemia.

Cancer Discov. 2023 Nov 02.

Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations.

Andreas Varkaris, Ferran Fece de la Cruz, Elizabeth E Martin, Bryanna L Norden, Nicholas Chevalier, Allison M Kehlmann, Ignaty Leshchiner, Haley Barnes, Sara Ehnstrom, Anastasia-Maria Stavridi, Xin Yuan, Janice S Kim, Haley Ellis, Alkistis Papatheodoridi, Hakan Gunaydin, Brian P Danysh, Laxmi Parida, Ioannis Sanidas, Yongli Ji, Kayao Lau, Gerburg M Wulf, Aditya Bardia, Laura M Spring, Steven J Isakoff, Jochen K Lennerz, Levi Pierce, Ermira Pazolli, Gad Getz, Ryan B Corcoran, Dejan Juric.

PIK3CA mutations occur in ~8% of cancers, including ~40% of HR-positive breast cancers, where the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinical acquired resistance to PI3Ka inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Ka-inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K-pathway, including PTEN loss and activating AKT1 mutations. Notably, while secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Ka-inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0704
Cancer Discov. 2023 11 01. 13(11): 2313-2315

A New Wave of PI3Kα Inhibitors.

Alison L Kearney, Neil Vasan.

SUMMARY: This is the first peer-reviewed report of an allosteric, mutant-selective PI3Kα inhibitor, STX-478, that reduces PIK3CA-mutant tumor growth in mice. However, in contrast to the FDA-approved PI3Kα isoform-selective inhibitor alpelisib, STX-478 does not induce hyperglycemia or other metabolic dysfunctions. See related article by Buckbinder et al., p. 2432 (7).

DOI: https://doi.org/10.1158/2159-8290.CD-23-0945
J Cell Sci. 2023 Nov 03. pii: jcs.261402. [Epub ahead of print]

Cholesterol regulates insulin-induced mTORC1 signaling.

Kolaparamba V Navyasree, Shikha T Ramesh, Perunthottathu K Umasankar.

  The rapid activation of the critical kinase, mechanistic target of rapamycin complex-1 (mTORC1) by insulin is key to cell growth in mammals, but the regulatory factors remain unclear. Here, we demonstrate that cholesterol plays a crucial role in the regulation of insulin-stimulated mTORC1 signaling. The rapid progression of insulin-induced mTORC1 signaling declines in sterol-depleted cells and restores in cholesterol-repleted cells. In insulin-stimulated cells, cholesterol promotes recruitment of mTORC1 onto lysosomes without affecting insulin-induced dissociation of the TSC complex from lysosomes, thereby enabling complete activation of mTORC1. We also show that under prolonged starvation conditions, cholesterol coordinates with autophagy to support mTORC1 reactivation on lysosomes thereby restoring insulin-responsive mTORC1 signaling. Further, we identify that Smith-Lemli-Opitz Syndrome (SLOS) patient fibroblasts and HeLa-SLOS model which are deficient in cholesterol biosynthesis exhibit defects in insulin-mTORC1 growth axis. These defects are rescued by supplementation of exogenous cholesterol or by expression of constitutively active Rag GTPase, a downstream activator of mTORC1. Overall, our findings propose novel signal integration mechanisms to achieve spatial and temporal control of mTORC1-dependent growth signaling and their aberrations in disease.

Keywords:  Cholesterol; Insulin; Lysosome; Signaling; mTORC1

DOI:  https://doi.org/10.1242/jcs.261402
Mol Cancer Ther. 2023 Oct 31.

TAS0612, a novel RSK, AKT, and S6K inhibitor, exhibits antitumor effects in preclinical tumor models.

Koji Ichikawa, Satoshi Ito, Emi Kato, Naomi Abe, Takumitsu Machida, Junya Iwasaki, Gotaro Tanaka, Hikari Araki, Kentaro Wakayama, Hideki Jona, Tetsuya Sugimoto, Kazutaka Miyadera, Shuichi Ohkubo.

The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or re-expression of receptor-type tyrosine kinases (RTKs). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. Additionally, TAS0612 demonstrated the persistence of blockade of downstream growth and anti-apoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent re-expression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for cancer patients to improve clinical responses and overcome resistance mechanisms.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-1037
J Clin Invest. 2023 Nov 01. pii: e167861. [Epub ahead of print]133(21):

Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1.

Heng Du, Yu Chi Yang, Heng-Jia Liu, Min Yuan, John M Asara, Kwok-Kin Wong, Elizabeth P Henske, Mallika Singh, David J Kwiatkowski.

  The PI3K/AKT/mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit, likely owing to their lack of effects on 4EBP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multiomics analysis showed extensive effects of the bi-steric inhibitors in comparison with rapamycin. De novo purine synthesis was selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.

Keywords:  Cancer; Oncology; Therapeutics

DOI:  https://doi.org/10.1172/JCI167861
Vet Pathol. 2023 Oct 31. 3009858231207021

Review: The PI3K-AKT-mTOR signal transduction pathway in canine cancer.

Travis K Meuten, Gregg A Dean, Douglas H Thamm.

  Tumors in dogs and humans share many similar molecular and genetic features, incentivizing a better understanding of canine neoplasms not only for the purpose of treating companion animals, but also to facilitate research of spontaneously developing tumors with similar biologic behavior and treatment approaches in an immunologically competent animal model. Multiple tumor types of both species have similar dysregulation of signal transduction through phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB; AKT), and mechanistic target of rapamycin (mTOR), collectively known as the PI3K-AKT-mTOR pathway. This review aims to delineate the pertinent aspects of the PI3K-AKT-mTOR signaling pathway in health and in tumor development. It will then present a synopsis of current understanding of PI3K-AKT-mTOR signaling in important canine cancers and advancements in targeted inhibitors of this pathway.

Keywords:  AKT; cancer; dog; mechanistic target of rapamycin; neoplasia; phosphatidylinositol 3-kinase; tumor

DOI:  https://doi.org/10.1177/03009858231207021
Cancer Discov. 2023 Nov 02.

Discovery and clinical proof-of-concept of RLY-2608, a first-in-class mutant-selective allosteric PI3Ka inhibitor that decouples anti-tumor activity from hyperinsulinemia.

Andreas Varkaris, Ermira Pazolli, Hakan Gunaydin, Qi Wang, Levi Pierce, Alessandro A Boezio, Lucian DiPietro, Adam Frost, Fabrizio Giordanetto, Erika P Hamilton, Katherine Harris, Michael Holliday, Tamieka L Hunter, Amanda Iskandar, Yongli Ji, Alexandre Larivée, Jonathan R LaRochelle, Andre Lescarbeau, Fabien Llambi, Brenda Lormil, Mary M Mader, Brenton G Mar, Iain Martin, Thomas H McLean, Klaus Michelsen, Yakov Pechersky, Erika Puente-Poushnejad, Ramin Samadani, Alison M Schram, Kelley Shortsleeves, Sweta Swaminathan, Shahein Tajmir, Gege Tan, Yong Tang, Roberto Valverde, Bryan Wehrenberg, Jeremy Wilbur, Bret R Williams, Hongtao Zeng, W Patrick Walters, Beni B Wolf, David E Shaw, Donald A Bergstrom, James Watters, James S Fraser, Pascal D Fortin, D Randal Kipp.

PIK3CA (PI3Ka) is a lipid kinase commonly mutated in cancer, including ~40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Ka inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Ka. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Ka activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Ka. RLY-2608 inhibited tumor growth in PIK3CA mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Ka-related toxicities.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0944