- |||||||||| Estybon (rigosertib) / Onconova, SymBio Pharma, Knight Therap
Review, Journal: Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na). (Pubmed Central) - Apr 28, 2023
However, in recent years, some studies have shown that rigosertib may also interact with the PI3K/Akt pathway, act as a Ras-Raf binding mimetic (altering the Ras signaling pathway), as a microtubule destabilizing agent, or as an activator of a stress-induced phospho-regulatory circuit that ultimately hyperphosphorylates and inactivates Ras signaling effectors. Understanding the mechanism of action of rigosertib has potential clinical implications worth exploring, as it may help to tailor cancer therapies and improve patient outcomes.
- |||||||||| Journal: BICD2 phosphorylation regulates dynein function and centrosome separation in G2 and M. (Pubmed Central) - Apr 27, 2023
BICD2 phosphorylation is central for dynein recruitment to the nuclear envelope, centrosome tethering to the nucleus and centrosome separation in the G2 and M phases of the cell cycle. This work reveals adaptor activation through phosphorylation as crucial for the spatiotemporal regulation of dynein activity.
- |||||||||| cisplatin / Generic mfg.
Predictive molecular markers of chemoradiation resistance in cervical cancer. () - Apr 26, 2023 - Abstract #ASCO2023ASCO_5521;
Further, the phosphoproteomic profiling revealed dysregulation of DNA repair pathways which may be involved in treatment resistance. Targeting the activated kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM could combat treatment resistance in cervical cancer patients.
- |||||||||| BI2536 / Boehringer Ingelheim
Journal: Human Polo-like Kinase Inhibitors as Antiplasmodials. (Pubmed Central) - Apr 17, 2023
A kinase panel screen identified PfNEK3 as a shared target of these PLK1 inhibitors; however, phosphoproteome analysis confirmed distinct signaling pathways were disrupted by two structurally distinct inhibitors, suggesting PfNEK3 may not be the sole target. Genomic analysis of BI-2536-resistant parasites revealed mutations in genes associated with the starvation-induced stress response, suggesting BI-2536 may also inhibit an aminoacyl-tRNA synthetase.
- |||||||||| Ibrance (palbociclib) / Pfizer
Journal, Metastases: CCNE1 and PLK1 mediates resistance to palbociclib in HR+/HER2- metastatic breast cancer. (Pubmed Central) - Apr 17, 2023
We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.
- |||||||||| Benlysta (belimumab) / GSK, Darzalex (daratumumab) / J&J
Journal, IO biomarker: Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus. (Pubmed Central) - Apr 12, 2023
High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i. Modulation of interferon, STAT1, PLK1, B and plasma cell signatures showed promise as viable approaches to treat SLE, pointing to their importance in SLE pathogenesis.
- |||||||||| Journal: Cation-free siRNA-cored nanocapsules for tumor-targeted RNAi therapy. (Pubmed Central) - Apr 4, 2023
The developed nanocapsules not only showed capacities including efficient siRNA encapsulation, high stability in serum, and cancer cell targeting via cRGD modification, but also achieved an efficient tumor-targeted gene silencing in vivo. Importantly, unlike cationic carriers, the nanocapsules exhibited no cation-associated side effects.
- |||||||||| BI2536 / Boehringer Ingelheim
Journal: Polo-like kinase inhibitor BI2536 induces eryptosis. (Pubmed Central) - Mar 31, 2023
Cells also showed an abundance of ceramide and an increase of intracellular calcium. All these finding suggest that BI2536 provokes eryptosis in red blood cells, ostensibly in part due to Ca entry and ceramide accumulation.
- |||||||||| Journal: BRD4 promotes hepatic stellate cells activation and hepatic fibrosis via mediating P300/H3K27ac/PLK1 axis. (Pubmed Central) - Mar 28, 2023
Mechanistically, BRD4 deficiency inhibited PLK1 expression in activated LX2 cells, and ChIP and Co-IP assays revealed that BRD4 regulation of PLK1 was dependent on P300-mediated acetylation modification for H3K27 on the PLK1 promoter. In conclusion, BRD4 deficiency in the liver alleviates CCl-induced HF in mice, and BRD4 participates in the activation and reversal of HSCs through positively regulating the P300/H3K27ac/PLK1 axis, providing a potential insight for HF therapy.
- |||||||||| cisplatin / Generic mfg., paclitaxel / Generic mfg., gemcitabine / Generic mfg.
Journal, Tumor mutational burden, BRCA Biomarker, PD(L)-1 Biomarker, IO biomarker: Performance of a PLK1-based immune risk model for prognosis and treatment response prediction in breast cancer. (Pubmed Central) - Mar 25, 2023
In conclusion, BRD4 deficiency in the liver alleviates CCl-induced HF in mice, and BRD4 participates in the activation and reversal of HSCs through positively regulating the P300/H3K27ac/PLK1 axis, providing a potential insight for HF therapy. This PLK1-based immune risk model can effectively predict the prognosis and tumor progression of BRCA, identify gene mutations, and evaluate patient's response toward immunotherapy and chemotherapy regimens.
- |||||||||| Journal: Phospho PTEN mediated dephosphorylation of mitotic kinase PLK1 and Aurora Kinase A prevents aneuploidy and preserves genomic stability. (Pubmed Central) - Mar 24, 2023
Interestingly, we observed that p-PTEN localized to spindle poles along with PLK1 and Aurora Kinase A. Further depletion of phosphorylation and phosphatase activity of PTEN increases the expression of p-Aurora Kinase A (T288) and p-PLK1 (T210), compared to cells expressing wild-type PTEN. Again, wild-type PTEN but not phosphorylation-dead mutant is able to physically interact with PLK1 and Aurora Kinase A. Thus, our study suggests that the phosphorylation-dependent interaction of PTEN with PLK1 and Aurora Kinase A causes dephosphorylation of those mitotic kinases and by lowering their hyperphosphorylation status, PTEN prevents aberrant chromosome segregation in metaphase.
- |||||||||| Journal: PLK1 regulates CtIP and DNA2 interplay in long-range DNA end resection. (Pubmed Central) - Mar 24, 2023
The integrity of S723 in CtIP is necessary for the stimulation of DNA2, and phosphorylation of CtIP by PLK1 in vitro is consequently inhibitory, explaining why PLK1 restricts long-range resection. Our data support a model in which CDK-dependent phosphorylation of CtIP activates resection by MRN in S phase, and PLK1-mediated phosphorylation of CtIP disrupts CtIP stimulation of DNA2 to attenuate long-range resection later at G2/M.
- |||||||||| tuvusertib (M1774) / EMD Serono
Molecular pharmacology and broad synergy of the novel ATR inhibitor M1774 with DNA damaging anticancer agents (Section 34; Poster Board #14) - Mar 14, 2023 - Abstract #AACR2023AACR_7995;
As a single agent, we found that M1774 suppresses cancer cell viability at nanomolar concentrations with a potency higher than ceralasertib and berzosertib, but lower than gartisertib (M4344) and elimusertib in the small cell lung cancer (SCLC) cell lines H146, H82, and DMS114...Low doses of M1774 significantly synergized with the clinical TOP1 inhibitor SN-38, the TOP2 inhibitor etoposide, cisplatin, and the PARP inhibitor talazoparib in SCLC cell lines...The synergistic efficacy between M1774 and DNA-damaging agents was confirmed in SCLC patient-derived organoids, colon cancer patient-derived organoids, and H82 SCLC xenografts. Together, these results provide insights into the molecular mechanism and potential combination strategies for M1774 in cancer therapy.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs
Nano-immunotherapy targeting PD-L1, PLK1, and TLR9 for treatment of non-small cell lung cancer (Section 22; Poster Board #22) - Mar 14, 2023 - Abstract #AACR2023AACR_7456;
ARAC-02 co-delivers a polo-like kinase 1 (PLK1)-targeted therapy (volasertib), a PD-L1 antibody, and the immune-stimulant CpG...Importantly, intravenous infusions of the platform was also found to be safe in a preliminary toxicology study in non-human primates. Due to its unique ability to catalyze various steps of the adaptive immune response, ARAC-02 is anticipated to provide superior outcomes in NSCLC and a broad range of tumor types regardless of baseline PD-L1 expression.
- |||||||||| Undisclosed PLK4 inhibitor / ORIC Pharma
Selective PLK4 inhibition demonstrates synthetic lethality in TRIM37 amplified neuroblastoma and breast cancer models while less selective inhibitors do not (Section 17; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_7174;
In cell viability assays, selective PLK4 inhibitors were potent in the parental G95 cells and lost activity in L95 cells, unlike less selective inhibitors whose potency did not depend on PLK4. Oral dosing of a selective PLK4 inhibitor resulted in tumor growth inhibition in TRIM37 high xenograft tumors with no body weight loss.In summary, we have discovered that highly selective small molecule inhibitors of PLK4 confirm the potential of the synthetic lethal impact in treating tumors with high levels of TRIM37.
- |||||||||| volasertib (NBL-001) / Oncoheroes, Notable Labs, Zelboraf (vemurafenib) / Roche
PLK1 promotes the metastasis and drug resistance in melanoma (Section 17; Poster Board #10) - Mar 14, 2023 - Abstract #AACR2023AACR_7173;
Our in vitro and in vivo experiments have shown an improved efficacy of this combined therapy on inhibition of cell proliferation, induction of cell death, and suppression of cell metastasis compared to mono-treatment. In short, our data has indicated PLK1 as a potent and promising target in cancer treatment.
- |||||||||| onvansertib (PCM-075) / Cardiff Oncology, volasertib (NBL-001) / Oncoheroes, Notable Labs
Targeting PLK1 effectively suppresses growth of small cell lung cancer (Section 17; Poster Board #8) - Mar 14, 2023 - Abstract #AACR2023AACR_7171;
Volasertib achieved significant tumor growth inhibition relative to control in H526 xenografts...The combination of PLK1i with standard chemotherapeutic agents identified promising synergy of the combination of onvansertib and paclitaxel...CRISPR knockout of YAP1 in this cell line enhanced SW1271 sensitivity to PLK1i suggesting that YAP1 expression as a marker of vulnerability to PLK1i could be context dependent especially when co-occurring with TP53 mutations. The mechanism of this interaction will be discussed.
- |||||||||| Plk1 phosphorylation of PHGDH to regulate serine metabolism (Section 7; Poster Board #4) - Mar 14, 2023 - Abstract #AACR2023AACR_6375;
As a compensatory response, cells with an elevated level of Plk1 significantly increase the uptake of serine to produce more sphingosines, which are pivotal metabolites for the growth of cancer cells. Our finding may provide guidance on how to target de novo biosynthesis of serine, serine uptake or sphingosine metabolism to treat advanced prostate cancer.
- |||||||||| A novel gene regulatory network model identifies master regulators in cancer (Section 33; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_5758;
A reduced GRN with only accurately predicted genes is obtained for each cluster, followed by linking GRNs to each other through TFs and kinases that are featured in other GRNs; where betweenness centrality measures of the resulting directed graph identifies disease-specific master regulators. MYC, STAT3, CREB1, POLR2A, PLK1, and TP53 are found to be key hubs in MM network; similar analyses are being conducted for other cancers featured in TCGA.
- |||||||||| vincristine / Generic mfg.
ReCorDE: A novel computational framework to discover potential combinations of anti-cancer drugs (Section 32; Poster Board #21) - Mar 14, 2023 - Abstract #AACR2023AACR_5737;
With a correlation coefficient of 0.77, vincristine and YK-4-279, an EWS-FLI1/RNA Helicase A inhibitor, had the lowest computed p-value of of 1.39 x 10-120... Our framework, ReCorDE, demonstrates that finding potential drug combinations and characterizing novel, frequently perturbed pathways outside of a drug's primary mechanisms of action can be accomplished by identifying correlated drug-drug pairs from large, publicly accessible databases.
- |||||||||| RPL27 augments growth and stemness properties in colorectal cancer through PLK1 signaling (Section 4; Poster Board #12) - Mar 14, 2023 - Abstract #AACR2023AACR_5414;
Our framework, ReCorDE, demonstrates that finding potential drug combinations and characterizing novel, frequently perturbed pathways outside of a drug's primary mechanisms of action can be accomplished by identifying correlated drug-drug pairs from large, publicly accessible databases. Taken together, these findings indicate that RPL27 contributes to promotion of CRC growth and stemness through PLK1 signaling and that targeting RPL27 could be a next-line therapeutic strategy for both primary CRC treatment and prevention of metastasis and/or recurrence.
- |||||||||| Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via upregulation of DIO2 (Section 9; Poster Board #6) - Mar 14, 2023 - Abstract #AACR2023AACR_5250;
Furthermore, this phenomenon is verified by in vivo mouse experiment using intravenous injection of DIO2-depleted cancer cells. Taken together, these results identify phosphorylation of AHR by PLK1 as a mechanism that leads to progression of LUAD.
- |||||||||| onvansertib (PCM-075) / Cardiff Oncology
Plk1 signaling as a therapeutic target for HPV- head and neck cancer (Section 19; Poster Board #23) - Mar 14, 2023 - Abstract #AACR2023AACR_5056;
Therefore, in this study we sought to establish if Plk1 inhibition with onvansertib (currently in Phase I/II clinical trials) alone and in combination with radiation would inhibit HPV- and HPV+ HNSCC growth...Our findings that HPV+ HNSCC cells are more resistant to Plk1 inhibition than HPV- HNSCC cells provides novel mechanistic insight into these disease subtypes. As HPV- HNSCC is typically more resistant to standard therapies, these results support a novel combinatorial approach using an already approved Plk1 inhibitor with radiation to improve HPV- HNSCC patient outcomes.
- |||||||||| adavosertib (AZD1775) / AstraZeneca
Discovery and development of a potent and highly selective WEE1 inhibitor IMP7068 (Section 31; Poster Board #4) - Mar 14, 2023 - Abstract #AACR2023AACR_4526;
P1
Anti-tumor efficacy of IMP7068 has been demonstrated in mice CDX models of colorectal LoVo, non-small cell lung cancer NCI-H1299 and a PDX model of uterine UT5318 with good dose-response tumor inhibition and tolerability. IMP7068 is currently in a phase I study to evaluate its safety, tolerability, pharmacokinetics, and anti-tumor activity in patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT04768868).
- |||||||||| BI2536 / Boehringer Ingelheim, volasertib (NBL-001) / Oncoheroes, Notable Labs
Preclinical examination of PLK1 inhibitors for the treatment of diffuse midline gliomas (Section 15; Poster Board #9) - Mar 14, 2023 - Abstract #AACR2023AACR_3842;
Together, these data indicate that targeting PLK1 is a highly promising therapeutic strategy to arrest DMG tumorgenicity. This data has formed the basis for a planned international Phase 1/2 trial of the PLK1 inhibitor volasertib in combination with radiotherapy in paediatric patients with DMG.
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