PI3K inhib 
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  • ||||||||||  voxtalisib (SAR245409) / Sanofi
    A genome wide CRISPR-Cas9 screen identifies mediators of resistance to dual PI3K/mTOR inhibition in glioblastoma multiforme (Section 23) -  Mar 5, 2024 - Abstract #AACR2024AACR_8085;    
    The current standard of care, consisting of surgery, radiation, and temozolomide (TMZ), has remained unchanged for over the past 15 years despite its limited efficacy and the serious therapy-related adverse events associated to this regimen...To elucidate mechanisms of resistance to PI3K inhibition in GBM, we used a genome-wide functional CRISPR-Cas9 knockout screen to identify genes that mediate resistance to the dual PI3K/mTOR inhibitor XL765 in PTEN-null SF295 GBM cells...Using orthogonal approaches, we will functionally validate our candidate hits through mechanistic studies, with patient-derived models, and with in vivo orthotopic xenografts. Our findings will elucidate novel mechanisms of resistance to PI3K/mTOR inhibition in GBM and will streamline rational drug combinations aimed to overcome resistance, thus eventually maximizing therapeutic responses to PI3K inhibitors in GBM.
  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Aliqopa (copanlisib) / Bayer
    CRISPR/Cas9 screening identifies genes affecting the sensitivity to the copanlisib/venetoclax combination in lymphoma cells (Section 23) -  Mar 5, 2024 - Abstract #AACR2024AACR_8080;    
    P1, P1/2
    Our findings will elucidate novel mechanisms of resistance to PI3K/mTOR inhibition in GBM and will streamline rational drug combinations aimed to overcome resistance, thus eventually maximizing therapeutic responses to PI3K inhibitors in GBM. A genome-wide genetic screening identified genes modulating the lymphoma cells response to the copanlisib/venetoclax combination, providing novel therapeutic targets or biomarkers.
  • ||||||||||  LY294002 / Eli Lilly
    HtrA3 promotes malignant progression of colorectal cancer via PI3K-AKT-FOXO1 signaling pathway (Section 45) -  Mar 5, 2024 - Abstract #AACR2024AACR_4952;    
    In HCT116 cells with high HtrA3 levels, there was an increase in p-PI3K, p-AKT, and p-FOXO1, which reduced upon treatment with the PI3K inhibitor LY294002...This study confirms that HtrA3's overexpression in CRC cells promotes their proliferation, migration, and invasion by activating the PI3K-AKT-FOXO1 signaling pathway. Therefore, HtrA3 could be a significant factor in the advancement of CRC and may serve as a potential prognostic marker for guiding targeted CRC therapies.
  • ||||||||||  RMC-5552 / Revolution Medicines, MRTX1133 / BMS
    The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer (Section 6) -  Mar 5, 2024 - Abstract #AACR2024AACR_4631;    
    Inhibiting the PI3K-AKT-mTOR axis alongside KRASG12D inhibition (MRTX1133) induced a robust, synergistic apoptotic response in KRASG12D tumor cell lines of varying sensitivity to KRASG12D inhibition alone, highlighting a potential combinatorial approach to override intrinsic resistance to KRASG12D inhibitors. Our preclinical data identify treatment vulnerabilities and suggest patient selection strategies for combination approaches that should be i) contextualized to individual RAS mutants, and ii) tailored to their downstream signaling programs.
  • ||||||||||  Piqray (alpelisib) / Novartis, inavolisib (GDC-0077) / Roche
    Discovery of a novel and potent mutant-selective inhibitor of PI3K? (Section 25) -  Mar 5, 2024 - Abstract #AACR2024AACR_4115;    
    with good drug-like properties that support further development of SNV-002 for treatment of cancers driven by oncogenic PI3K? mutations.
  • ||||||||||  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.