- |||||||||| Piqray (alpelisib) / Novartis
Novel long-acting covalent PI3K? inhibitors boost potential action in cancer (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_4114;
The new class of irreversible PI3K? inhibitors have a unique pharmacology among PI3K inhibitors characterized by strong decoupling of drug exposure from efficacy which may provide opportunities to lower treatment burden in patients.
- |||||||||| Piqray (alpelisib) / Novartis
Development of highly potent, covalent, and selective inhibitors to target PI3K? in cancer (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_4113;
selective inhibitors in models with PTEN loss and demonstrates that persistent inhibition across the PI3K pathway is required for efficacy. In summary, the new cPI3K?i display outstanding specificity and cellular activity in PIK3CA-mutated cancer cells, and support the further development of cPI3K?i as future clinical candidates and an alternative to established reversible inhibitors.
- |||||||||| Aliqopa (copanlisib) / Bayer
Co-alterations in PIK3CA and ARID1A lead to enhanced sensitivity to PI3K inhibition (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_4111;
ARID1A loss along with PIK3CA mutation leads to greater PI3K inhibition response most likely due to enhanced induction of apoptosis. Further confirmation of this enhanced sensitivity is required with better in vitro models such as patient-derived cancer organoids.
- |||||||||| A pro-oncogenic RAS-GTP:RAN-GAP complex facilitates nuclear protein export and has clinical implications (Section 29) - Mar 5, 2024 - Abstract #AACR2024AACR_4093;
Analysis of a KRAS mutant cell line from which the DLC1 gene has been disrupted by CRISPR-Cas9 technology indicates that DLC1 makes an important contribution to the growth inhibition by inhibitors that reduce nuclear protein export. These findings establish nuclear protein export as a critical, pro-oncogenic, non-canonical RAS function that is mediated by the RAS-GTP:RAN-GAP complex and provide a mechanistic explanation for poor clinical responses to combined inhibition of MEK and PI3K, which do not regulate the nuclear protein activity identified in this study.
- |||||||||| Lumakras (sotorasib) / Amgen
Acquired resistance to sotorasib in KRASG12C mutant NSCLC is vulnerable to PI3K-mTOR pathway inhibition and regulated by 4E-BP1 (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4015;
Both resistant PDXOs and cell lines showed resistance to adagrasib, another selective, KRASG12C inhibitor...Inhibition of PI3K, AKT and mTOR by copanlisib, MK2206 and everolimus respectively was synergistic with sotorasib in AR cells and PDXOs, with copanlisib being the most effective...When copanlisib was combined with sotorasib in treating the resistant TC303AR, TC314AR PDXs, H358AR CDX and H23AR xenograft tumors, antitumor effects were observed in every model. Inhibition of the PI3K pathway at different nodes is a vulnerability in KRASG12C mutant NSCLC with sotorasib AR and p4E-BP1 is a mediator of sotorasib resistance
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4011;
The mutant HRAS inhibitor tipifarnib blocked PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cancer cell lines; covalent KRASG12C inhibitors blocked MEK signaling and synergized with PI3K inhibitors in KRASG12C- mutated cell lines...Dual knock-out of WT RAS isoforms in KRAS- and HRAS-mutated cancer cell lines reduced PI3K signaling in KRAS-mutant cell lines and MAPK signaling in HRAS-mutant cell lines and reduced proliferation, confirming our findings in MEF cells. Overall, our data highlight the critical role of WT RAS isoforms in supporting mutant RAS signaling and should be considered when designing combination therapies in RAS-mutated cancers.
- |||||||||| Piqray (alpelisib) / Novartis, Tasigna (nilotinib) / Novartis, Inhibikase
The N6-methyladenine-long noncoding RNA axis promotes drug resistance through PI3k signaling in leukemia (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_4001;
Treatment with PI3K inhibitor alpelisib sensitizes TKI-resistant cells to TKI-induced cell death and reduces leukemia burden in mice via downregulation of F2R, ITGA2, and COL6A1. In conclusion, our findings add a new layer to the complexity of mechanisms regulating leukemia cell fate under TKI selection and raise the possibility that the m6A-regulated lncRNAs represents a new non-genetic factor to affect the development and maintenance of TKI resistance; our discoveries identify a promising therapeutic target, the m6A-lncRNAs axis, for specifically the most challenging patient subpopulations who are TKI non-responders/relapsed but do not carry the acquired mutations on top of BCR/ABL; our results also uncover a strong predictor, m6A-regulated lncRNA-PI3K axis, for poorer prognosis and failure in drug response which might be a pan-cancer mechanism.
- |||||||||| Piqray (alpelisib) / Novartis, Xalkori (crizotinib) / Pfizer
Dual targeting of the PI3K-AKT pathway in triple-negative breast cancer (Section 35) - Mar 5, 2024 - Abstract #AACR2024AACR_3507;
Targeting upregulated proteins in a cohort of TP53-MUT/PIK3CA-MUT patients may improve sensitivity to alpelisib via dual inhibition of PI3K-AKT pathway activation. Protein analysis will uncover the mechanisms of synergy observed between alpelisib and crizotinib, and the therapeutic potential of the combination will be experimentally investigated in vivo.
- |||||||||| Aliqopa (copanlisib) / Bayer
BCLxL inhibition enhances copanlisib response in colorectal cancer (Section 15) - Mar 5, 2024 - Abstract #AACR2024AACR_2869;
High BCLxL expression is a sign of poor prognosis for PIK3CA mutant CRC. Inhibiting BCLxL can enhance the sensitivity of PI3K inhibition in PIK3CA mutant cancers and deserves further investigation clinically.
- |||||||||| atirmociclib (PF-07220060) / Pfizer
Preclinical development of the CDK4 selective inhibitor PF-07220060: Increased CDK4 versus CDK6 inhibition leads to improved anti-tumor efficacy at therapeutic concentrations (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_2718;
PF-07220060 is a selective inhibitor of CDK4, displaying ~20-fold and ~4-fold increased selectivity for CDK4 versus CDK6 when compared to palbociclib and abemaciclib/ribociclib, respectively...PF-07220060 sensitizes HR+ HER2- breast cancer to the estrogen inhibitor, fulvestrant and the degrader, ARV-471 (vepdegestrant)...Similarly, PF-07220060 sensitizes prostate cancer to the androgen receptor antagonist, enzalutamide...Further addition of the PI3K inhibitor alpelisib was sufficient to enforce tumor shrinkage in vivo...Even so, in these instances, PF-07220060's efficacy remained comparable to palbociclib's when both drugs were used at their therapeutic doses. We conclude that PF-07220060's anti-tumor efficacy is broadly superior to currently approved dual CDK4/6 inhibitors.
- |||||||||| Journal: Slit2 suppresses endotoxin-induced uveitis by inhibiting the PI3K/Akt/IKK/NF-?B pathway. (Pubmed Central) - Mar 5, 2024
In conclusion, the intravitreal injection of rhSlit2 alleviated EIU-related inflammation in Sprague-Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS-induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF-?B signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.
- |||||||||| MK-2206 / Merck (MSD), Zydelig (idelalisib) / Gilead
Preclinical, Journal: Glucose Metabolism in Acute Myeloid Leukemia Cell Line Is Regulated via Combinational PI3K/AKT/mTOR Pathway Inhibitors. (Pubmed Central) - Mar 4, 2024
A combination of PI3K/AKT/mTOR pathway inhibitors regulates the expression of genes involved in glycolysis, pyruvate dehydrogenase complex (PDH), and the tricarboxylic acid (TCA) cycle and interferes with metabolic reprogramming and immune evasion mechanisms of AML leukemic cells. Combinational therapy approaches to block these pathways might be a promising and novel therapeutic strategy for targeting the metabolic requirements of AML cells.
- |||||||||| Journal: Therapeutic effects of coptisine derivative EHLJ7 on colorectal cancer by inhibiting PI3K/AKT pathway. (Pubmed Central) - Mar 4, 2024
The key findings in this study are listed as follows: (1) EHLJ7 exerts superior anti-tumor effect with good safety on Xenograft tumor model and CRC model; (2) EHLJ7 exerted its anti-CRC effect by specifically inhibiting PI3K/AKT pathway and apoptosis in vivo and in vitro. In summary, we demonstrated that EHLJ7 exerts therapeutic effect against CRC by PI3K/AKT pathway, which made it possible as a potentially effective compound for the treatment of CRC.
- |||||||||| Piqray (alpelisib) / Novartis
Journal: Dissecting the Interaction Fingerprints and Binding Affinity of BYL719 Analogs Targeting PI3K?. (Pubmed Central) - Mar 1, 2024
Binding affinities predicted via thermodynamic integration (TI) are in good agreement with previously reported IC50s. Yet, computationally demanding techniques such as TI might not always be the most efficient approach for affinity prediction, as in our case study, fast high-throughput techniques were capable of classifying compounds as active or inactive, and one docking approach showed accuracy comparable to TI.
- |||||||||| Journal: GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1. (Pubmed Central) - Feb 28, 2024
In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids.
- |||||||||| Review, Journal: Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers. (Pubmed Central) - Feb 28, 2024
However, the limited clinical efficacy of these inhibitors, intolerable toxicities, and acquired resistances limit the clinical application of PI3K inhibitors. This review discusses the PI3K signaling pathway, alterations in the PI3K pathway causing carcinogenesis, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, challenging issues, and future directions of PI3K pathway inhibitors.
- |||||||||| Piqray (alpelisib) / Novartis
401-B - Clinical Pearl 2: Best Practices (Ballroom A) - Feb 27, 2024 - Abstract #HOPA2024HOPA_94;
Session Description: The PI3K inhibitor alpelisib, indicated in PI3KC-mutated, hormone positive advanced breast cancer, has a known incidence of hyperglycemia in up to 79% of patients, with up to 39% of patients experiencing grade 3-4 hyperglycemia. Timely identification and proper management of hyperglycemia is critical to maintain treatment consistency and safety.This session will review alpelisib-induced hyperglycemia, prevention methods, hyperglycemia evaluation considerations, and management strategies to reduce treatment interruptions and discontinuations.Learning Objectives:
- |||||||||| colchicine / Generic mfg.
Journal: Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1. (Pubmed Central) - Feb 24, 2024
In Syrian hamsters (Mesocricetus auratus) infected with SARS-CoV-2, inhibition of SP1 by either mithramycin A or colchicine resulted in reduced viral replication and tissue injury. In summary, our study uncovers a novel function of SP1 in the regulation of ACE2 expression and identifies SP1 as a potential target to reduce SARS-CoV-2 infection.
- |||||||||| LY294002 / Eli Lilly
Preclinical, Journal: Antidiabetic Effect of Urolithin A in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Glucose Intolerance. (Pubmed Central) - Feb 23, 2024
This elevation in GU by UroA treatment was partially inhibited by the concurrent addition of LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K) which activates Akt (PKB: protein kinase B) or Compound C, an inhibitor of 5'-adenosine monophosphate-activated protein kinase (AMPK)...UroA was demonstrated to alleviate glucose intolerance. These results suggest that UroA is a biofactor with antihyperglycemic effects in the T2D state.
- |||||||||| Journal: Genetic loss of Nrf1 and Nrf2 leads to distinct metabolism reprogramming of HepG2 cells by opposing regulation of the PI3K-AKT-mTOR signalling pathway. (Pubmed Central) - Feb 21, 2024
Further experiments revealed that such distinctive metabolic programming of between Nrf1?-/- and Nrf2-/- resulted from substantial activation of the PI3K-AKT-mTOR signalling pathway upon the loss of Nrf1, leading to increased expression of critical genes for the glucose uptake, glycolysis, the pentose phosphate pathway, and the de novo lipid synthesis, whereas deficiency of Nrf2 resulted in the opposite phenomenon by inhibiting the PI3K-AKT-mTOR pathway. Altogether, these provide a novel insight into the cancer metabolic reprogramming and guide the exploration of a new strategy for targeted cancer therapy.
- |||||||||| Piqray (alpelisib) / Novartis
Journal, Tumor cell: Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells. (Pubmed Central) - Feb 20, 2024
We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide...Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner...Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.
- |||||||||| spironolactone / Generic mfg.
Targeting Inflammation in Pulmonary Artery Hypertension: A High-throughput Small Molecule Screen for Compounds Degrading Xeroderma Pigmentosum Group B Protein (XPB) (San Diego Convention Center, Room 6E (Upper Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_7324;
Spironolactone (SPL) increases survival in patients with left heart failure where it improves endothelial function and reduces inflammation...Candidates belonged to a variety of different drug classes, including inhibitors of PI3K, the L-type calcium channel, integrins, heat shock proteins, and several types of growth factors.Conclusion High-throughput small molecule screening unveiled a relatively exclusive group of compounds that may induce XPB degradation. Candidate XPB degraders need to be confirmed in secondary assays and tested for effects on inflammatory gene transcription.
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