PAK4-targeted PROTACs in clear cell renal cell carcinoma: a two-for-one targeted and immune therapy? DOI Creative Commons
Ziad Bakouny, David A. Braun, Ed Reznik

и другие.

EBioMedicine, Год журнала: 2024, Номер 105, С. 105218 - 105218

Опубликована: Июнь 25, 2024

Renal cell carcinoma (RCC) affects approximately 82,000 patients and causes over 15,000 deaths in the United States per year.1Siegel R.L. Giaquinto A.N. Ahmedin J. Cancer statistics, 2024.CA J Clin. 2024; 74: 12-49https://doi.org/10.3322/CAAC.21820Crossref PubMed Scopus (0) Google Scholar Clear RCC (ccRCC) accounts for around 75% of cases is characterized by near-ubiquitous biallelic inactivation VHL, which ultimately activates a pseudohypoxia program driven hypoxia inducible factor (HIF) family. The management with advanced or metastatic ccRCC has been revolutionized therapies targeting HIF-VEGF axis immune checkpoint inhibitors PD-1 CTLA-4 axes. Combinations these pathways have thus far proven to be most effective strategies treatment ccRCC. Despite improvements ccRCC, still eventually progress. Further improving outcomes will likely require combinations that incorporate novel targets, would ideally synergistic additive activity as well minimally overlapping toxicities.2Saliby R.M. Saad E. Labaki C. et al.Novel targeted renal carcinoma: building on successes vascular endothelial growth mTOR inhibition.Hematol Oncol Clin North Am. 2023; 37: 1015-1026https://doi.org/10.1016/J.HOC.2023.05.022Summary Full Text PDF Scholar,3Braun D.A. Bakouny Z. Hirsch L. al.Beyond conventional immune-checkpoint inhibition — immunotherapies carcinoma.Nat Rev Oncol. 2021; 18: 199-214https://doi.org/10.1038/s41571-020-00455-zCrossref (189) In this study, Xu al. developed tested efficacy toxicity proteolysis chimera (PROTAC) degrades P21-activated kinase-4 (PAK4) ccRCC.4Xu S. Ma B. Jian Y. Yao Wang Fan Development PAK4-targeting PROTAC therapy: concurrent cancer proliferation enhancement response.eBioMedicine. 104: 105162https://doi.org/10.1016/j.ebiom.2024.105162Summary (1) PAK4 serine/threonine kinase, one six PAKs all share structural functional homology. overexpressed multiple cancers associates worse various tumor types. roles cancer, including promotion invasion, metastasis, proliferation, epithelial-to-mesenchymal transition through activation Wnt/Beta-catenin, MAPK, PI3K/AKT pathways.5Won S.Y. Park J.J. Shin E.Y. Kim E.G. signaling health disease: defining PAK4–CREB axis.Exp Mol Med. 2019; 51: 1-9https://doi.org/10.1038/s12276-018-0204-0Crossref (54) also shown inhibit ccRCC6Aboud O.A. Chen C.H. Senapedis W. Baloglu Argueta Weiss R.H. Dual specific NAMPT KPT-9274 decreases kidney growth.Mol Ther. 2016; 15: 2119https://doi.org/10.1158/1535-7163.MCT-16-0197Crossref (116) potentiate immunotherapy responses other types.7Abril-Rodriguez G. Torrejon D.Y. Liu al.PAK4 improves blockade immunotherapy.Nat Cancer. 1: 46-58https://doi.org/10.1038/s43018-019-0003-0Crossref (91) evaluated its line mouse models patient-derived organoids. They studied profile pharmacokinetics vivo goal translating PAK4-targeted PROTAC's use Multiple small molecule are development, though insufficient inadequate selectivity limited their potential date.8Li Lu Q. Xie Yu Zhang A. Recent advances development p21-activated kinase 4 anti-tumor agents.Front Pharmacol. 2022; 13https://doi.org/10.3389/FPHAR.2022.956220Crossref PROTACs promising approach selectively effectively degrade oncogenic targets could circumvent limitations classical inhibitors. build approaches protein degradation, namely immunomodulatory imide-containing drugs (IMiDs) selective estrogen receptor degraders (SERDs) Food Drug Administration (FDA)-approved myeloma breast respectively.9Fang Han al.Targeted degrader cancer: advances, challenges, opportunities.Trends Pharmacol Sci. 44: 303-317https://doi.org/10.1016/j.tips.2023.03.003Summary (14) currently phase II III clinical trials, degradation androgen prostate (Luxdegalutamide) (Vepdegestrant).10Wang X. Qin Z.L. Li N. al.Annual review anticancer agents 2022.Eur Med Chem. 267116166https://doi.org/10.1016/J.EJMECH.2024.116166Crossref To ccRCC-specific loss VHL (another E3 ubiquitin ligase commonly used PROTACs), leveraged MDM2 ligase. authors demonstrate vitro (in organoids) increases CD8+ T infiltration into tumors (Fig. 1). show effect mediated unaffected PROTAC. propose induces an response can combining inhibitor, given highly interesting add way armamentarium available agents. direct effects appear seemingly tolerable may allow it combined VEGF-targeted tyrosine and/or While claim potentiating inhibitors, not fully substantiated data despite being previously observed Further, whether humans sufficient single agent warrant further remains seen, particularly since existing either failed trials date early stages development. Finally, present evidence but presented effectiveness forms (i.e. non-clear RCC) sparse warrants investigation. conclusion, study develops potentially represent pathway inhibition. both target cell-autonomous driver activate appealing, investigation determine safety Conceptualization: Ziad Bakouny. Supervision: David Braun, Ed Reznik, Ari Hakimi. Writing: Bakouny, All read approved final manuscript. following report competing interests (all outside submitted work): Z.B.: Honoraria from UpToDate; Associate Editor at Journal Clinical Oncology Informatics (JCO CCI); co-chair American Society Oncology's International Medical Graduate Community Practice (ASCO IMG CoP); co-founder Oncologists nonprofit non-governmental organization. D.A.B.: advisory board fees Exelixis, AVEO, Eisai, Elephas, equity Fortress Biotech (subsidiary) CurIOS Therapeutics, consulting/personal Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, Rock, research support Exelixis AstraZeneca, work. E.R.: Consulting/personal Xontogeny, llc, A.A.H.: funding This work was supported National Institute Center Core (grant P30-CA008748) supporting Memorial Sloan Kettering Center. responseThis peptide drug only curtails microenvironment enhances response. Our paves innovative cancer. Full-Text Open Access

Язык: Английский

Knockout of p21-Activated Kinase 4 Stimulates MHC I Expression of Pancreatic Cancer Cells via an Autophagy-Independent Pathway DOI Open Access
Yi Ma,

Chelsea Dumesny,

Li Dong

и другие.

Cancers, Год журнала: 2025, Номер 17(3), С. 511 - 511

Опубликована: Фев. 3, 2025

Background/Objectives: Pancreatic ductal adenocarcinoma (PDA) is one of the most malignant solid cancers. KRAS mutation accounts for over 90% cases. p21-activated kinases (PAKs) act downstream and are involved in tumorigenesis. The inhibition PAK4 suppresses PDA by stimulating tumor infiltration cytotoxic T cells. major histocompatibility complex class I (MHC I) a key presenting antigens to MHC degradation via autophagy promotes immune evasion pancreatic cancer. We investigated effect on expression autophagy. Methods: In this study, using proteomic analysis, fluorescence-activated cell sorting (FACS), immunoblotting, we examined knockout (KO) human cells identify mechanism stimulation inhibition. Results: found that KO increased two lines: MiaPaCa-2 PANC-1. also cancer However, chloroquine (CQ) did not affect apoptosis death. More importantly, CQ alter stimulated KO, indicating an autophagy-independent pathway. Conclusions: identified role cells, which independent

Язык: Английский

Процитировано

0
Phosphoproteomics identifies determinants of PAK inhibitor sensitivity in leukaemia cells DOI Creative Commons
Pedro Casado, Santiago Marfà, Marym M. Hadi

и другие.

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Март 13, 2025

Abstract Background The P21 activated kinases (PAK) are frequently dysregulated in cancer and have central roles oncogenic signalling, prompting the development of PAK inhibitors (PAKi) as anticancer agents. However, such compounds not reached clinical use because, at least partially, there is a limited mechanistic understanding their mode action. Here, we aimed to characterize functional molecular responses PAKi (PF-3758309, FRAX-486 IPA-3) multiple acute myeloid leukaemia (AML) models gain insights on biochemical pathways affected by these this disease identify determinants response patient samples. Methods We mined phosphoproteomic datasets primary AML, used proteomics phosphoproteomics profile impact immortalized (P31/Fuj MV4-11), AML cells from 8 patients. These omics were integrated with gene dependency data which proteins targeted necessary for proliferation AML. studied effect cell cycle progression, proliferation, differentiation apoptosis. Finally, input machine learning that predicted ex vivo two independent (with 36 50 cases, respectively) PF-3758309 markers response. Results found PAK1 activation– measured data– was predictive poor prognosis cases. most effective reducing inducing apoptosis lines. In lines cells, inhibited PAK, AMPK PKCA activities, reduced c-MYC transcriptional activity expression ribosomal proteins, FLT3 pathway FLT3-ITD mutated cells. STAT5 phosphorylation Tyr699. Functionally, cell-growth, induced apoptosis, blocked progression promoted model-dependent manner. ML modelling accurately classified samples sensitive or resistant treatment, highlighted PHF2 Ser705 robust biomarker. Conclusions summary, our define proteomic, immortalised suggest route personalise treatments based inhibitors.

Язык: Английский

Процитировано

0
The Peptide PROTAC Modality: A New Strategy for Drug Discovery DOI Creative Commons
Youmin Zhu, Yu Dai,

Yun-Cai Tian

и другие.

MedComm, Год журнала: 2025, Номер 6(4)

Опубликована: Март 24, 2025

ABSTRACT In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC provides new ideas for treating various diseases by inducing degradation target proteins. Especially peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review detailed description key components, mechanisms, design principles elaborates applications skin‐related diseases, oncology, other potential therapeutic fields, analyzes advantages challenges, looks forward future development prospects. The not only opens up paths development, but also solving resistance safety issues faced traditional small‐molecule drugs. Compared with PROTACs such as multitargeting, biodegradability, low toxicity, flexibility design. With deepening continuous maturity technology, are expected one important strategies discovery, providing hope treatment more intractable diseases. Peptide ushering era precision medicine.

Язык: Английский

Процитировано

0
The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma DOI Creative Commons
Yifan Zhang, Shengli Zhang, Hongbin Sun

и другие.

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Апрель 19, 2025

Abstract Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions reprogramming as central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, microenvironment-driven plasticity. This orchestrated rewiring cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T exhaustion myeloid-derived suppressor activation. Crucially, exhibits heterogeneity across histological subtypes intratumoral regions—a feature increasingly recognized determinant therapeutic resistance. Our review systematically deciphers molecular architecture metabolism, elucidating how VHL/HIF mutations, mTOR pathway dysregulation, epigenetic modifiers converge reshape glucose flux, droplet biogenesis, amino acid catabolism. We present novel insights into spatial zonation within tumors, where pseudohypoxic niches engage lactate shuttling cholesterol efflux adjacent vasculature, creating pro-angiogenic immunosuppressive microdomains. Therapeutically, we evaluate first-in-class inhibitors targeting rate-limiting enzymes de novo lipogenesis proposing biomarker-driven strategies overcome compensatory highlight synergy glutaminase PD-1 blockade reinvigorating CD8 + function, role lipid-loaded cancer-associated fibroblasts shielding tumors from ferroptosis. Finally, outline translational roadmap integrating multi-omics profiling, functional metabolomics, biology match vulnerabilities with precision therapies.

Язык: Английский

Процитировано

0
Advancements in delivery Systems for Proteolysis-Targeting Chimeras (PROTACs): Overcoming challenges and expanding biomedical applications DOI

Yawei Yu,

Weitong Hu,

Yihua Xu

и другие.

Journal of Controlled Release, Год журнала: 2025, Номер unknown, С. 113719 - 113719

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Design and optimization strategies of PROTACs and its Application, Comparisons to other targeted protein degradation for multiple oncology therapies DOI

M. Malarvannan,

S. Unnikrishnan,

S. Monohar

и другие.

Bioorganic Chemistry, Год журнала: 2024, Номер 154, С. 107984 - 107984

Опубликована: Ноя. 22, 2024

Язык: Английский

Процитировано

3
Peptides as Targeting Agents and Therapeutics: A Brief Overview DOI

Jalissa L. Warthen,

Michael Lueckheide

Biomacromolecules, Год журнала: 2024, Номер 25(11), С. 6923 - 6935

Опубликована: Окт. 24, 2024

The controllability and specificity of peptides make them ideal for targeting therapeutic delivery systems as agents that interfere with the essential functions pathogens tumors. Peptides can also mimic natural protein structures or parts thereof, agonize receptors, be conjugated to other molecules will self-assemble. In this short Review, we discuss research from last ten years into peptide use in three arenas: treatment cancer, pathogens, specific organs organelles. These studies demonstrate successful application

Язык: Английский

Процитировано

2
PAK4-targeted PROTACs in clear cell renal cell carcinoma: a two-for-one targeted and immune therapy? DOI Creative Commons
Ziad Bakouny, David A. Braun, Ed Reznik

и другие.

EBioMedicine, Год журнала: 2024, Номер 105, С. 105218 - 105218

Опубликована: Июнь 25, 2024

Renal cell carcinoma (RCC) affects approximately 82,000 patients and causes over 15,000 deaths in the United States per year.1Siegel R.L. Giaquinto A.N. Ahmedin J. Cancer statistics, 2024.CA J Clin. 2024; 74: 12-49https://doi.org/10.3322/CAAC.21820Crossref PubMed Scopus (0) Google Scholar Clear RCC (ccRCC) accounts for around 75% of cases is characterized by near-ubiquitous biallelic inactivation VHL, which ultimately activates a pseudohypoxia program driven hypoxia inducible factor (HIF) family. The management with advanced or metastatic ccRCC has been revolutionized therapies targeting HIF-VEGF axis immune checkpoint inhibitors PD-1 CTLA-4 axes. Combinations these pathways have thus far proven to be most effective strategies treatment ccRCC. Despite improvements ccRCC, still eventually progress. Further improving outcomes will likely require combinations that incorporate novel targets, would ideally synergistic additive activity as well minimally overlapping toxicities.2Saliby R.M. Saad E. Labaki C. et al.Novel targeted renal carcinoma: building on successes vascular endothelial growth mTOR inhibition.Hematol Oncol Clin North Am. 2023; 37: 1015-1026https://doi.org/10.1016/J.HOC.2023.05.022Summary Full Text PDF Scholar,3Braun D.A. Bakouny Z. Hirsch L. al.Beyond conventional immune-checkpoint inhibition — immunotherapies carcinoma.Nat Rev Oncol. 2021; 18: 199-214https://doi.org/10.1038/s41571-020-00455-zCrossref (189) In this study, Xu al. developed tested efficacy toxicity proteolysis chimera (PROTAC) degrades P21-activated kinase-4 (PAK4) ccRCC.4Xu S. Ma B. Jian Y. Yao Wang Fan Development PAK4-targeting PROTAC therapy: concurrent cancer proliferation enhancement response.eBioMedicine. 104: 105162https://doi.org/10.1016/j.ebiom.2024.105162Summary (1) PAK4 serine/threonine kinase, one six PAKs all share structural functional homology. overexpressed multiple cancers associates worse various tumor types. roles cancer, including promotion invasion, metastasis, proliferation, epithelial-to-mesenchymal transition through activation Wnt/Beta-catenin, MAPK, PI3K/AKT pathways.5Won S.Y. Park J.J. Shin E.Y. Kim E.G. signaling health disease: defining PAK4–CREB axis.Exp Mol Med. 2019; 51: 1-9https://doi.org/10.1038/s12276-018-0204-0Crossref (54) also shown inhibit ccRCC6Aboud O.A. Chen C.H. Senapedis W. Baloglu Argueta Weiss R.H. Dual specific NAMPT KPT-9274 decreases kidney growth.Mol Ther. 2016; 15: 2119https://doi.org/10.1158/1535-7163.MCT-16-0197Crossref (116) potentiate immunotherapy responses other types.7Abril-Rodriguez G. Torrejon D.Y. Liu al.PAK4 improves blockade immunotherapy.Nat Cancer. 1: 46-58https://doi.org/10.1038/s43018-019-0003-0Crossref (91) evaluated its line mouse models patient-derived organoids. They studied profile pharmacokinetics vivo goal translating PAK4-targeted PROTAC's use Multiple small molecule are development, though insufficient inadequate selectivity limited their potential date.8Li Lu Q. Xie Yu Zhang A. Recent advances development p21-activated kinase 4 anti-tumor agents.Front Pharmacol. 2022; 13https://doi.org/10.3389/FPHAR.2022.956220Crossref PROTACs promising approach selectively effectively degrade oncogenic targets could circumvent limitations classical inhibitors. build approaches protein degradation, namely immunomodulatory imide-containing drugs (IMiDs) selective estrogen receptor degraders (SERDs) Food Drug Administration (FDA)-approved myeloma breast respectively.9Fang Han al.Targeted degrader cancer: advances, challenges, opportunities.Trends Pharmacol Sci. 44: 303-317https://doi.org/10.1016/j.tips.2023.03.003Summary (14) currently phase II III clinical trials, degradation androgen prostate (Luxdegalutamide) (Vepdegestrant).10Wang X. Qin Z.L. Li N. al.Annual review anticancer agents 2022.Eur Med Chem. 267116166https://doi.org/10.1016/J.EJMECH.2024.116166Crossref To ccRCC-specific loss VHL (another E3 ubiquitin ligase commonly used PROTACs), leveraged MDM2 ligase. authors demonstrate vitro (in organoids) increases CD8+ T infiltration into tumors (Fig. 1). show effect mediated unaffected PROTAC. propose induces an response can combining inhibitor, given highly interesting add way armamentarium available agents. direct effects appear seemingly tolerable may allow it combined VEGF-targeted tyrosine and/or While claim potentiating inhibitors, not fully substantiated data despite being previously observed Further, whether humans sufficient single agent warrant further remains seen, particularly since existing either failed trials date early stages development. Finally, present evidence but presented effectiveness forms (i.e. non-clear RCC) sparse warrants investigation. conclusion, study develops potentially represent pathway inhibition. both target cell-autonomous driver activate appealing, investigation determine safety Conceptualization: Ziad Bakouny. Supervision: David Braun, Ed Reznik, Ari Hakimi. Writing: Bakouny, All read approved final manuscript. following report competing interests (all outside submitted work): Z.B.: Honoraria from UpToDate; Associate Editor at Journal Clinical Oncology Informatics (JCO CCI); co-chair American Society Oncology's International Medical Graduate Community Practice (ASCO IMG CoP); co-founder Oncologists nonprofit non-governmental organization. D.A.B.: advisory board fees Exelixis, AVEO, Eisai, Elephas, equity Fortress Biotech (subsidiary) CurIOS Therapeutics, consulting/personal Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, Rock, research support Exelixis AstraZeneca, work. E.R.: Consulting/personal Xontogeny, llc, A.A.H.: funding This work was supported National Institute Center Core (grant P30-CA008748) supporting Memorial Sloan Kettering Center. responseThis peptide drug only curtails microenvironment enhances response. Our paves innovative cancer. Full-Text Open Access

Язык: Английский

Процитировано

0