MCL1 overexpression

Finally, molecular dynamics simulations run for 100 ns were done using the GROMACS, version 5.0.7, with the CHARMM36 force field. MM-PBSA was used to assess binding affinity specificity in targeting Mcl-1 and Bcl-xL (B-cell lymphoma extra-large).

Our results suggest that FBXW7 affects autophagy through MCL1 in OSCC.

Likewise, CQ-induced MCL1 suppression and glycolysis inhibition resulted in higher cytotoxicity in CML KU812/HQ cells than in KU812 cells. Taken together, our data confirm that CQ inhibits MCL1 expression through the ERK/miR-29a/TTP/NOXA pathway, and that inhibition of glycolysis is positively correlated to higher cytotoxicity of CQ on HQ-selected CML cells.

5µM, KS18 demonstrated efficacy against bortezomib-resistant MM cells, outperforming other Mcl-1 inhibitors in clinical trials such as S63845, VU661013, and AZD5991. According to these results, KS18 may be able to overcome resistance by concentrating on Mcl-1. These encouraging findings have prompted the development of many models of drug-resistant MM and AML for in vivo evaluation of this potential chemical.

Additionally, NTX-301 treatment increased caspase-8 and cleaved-caspase-8 in AML cells independent of TP53 mutation status, consistence with reports showing caspase-8 hypermethylation in AML and supporting that activation of caspase-8-mediated extrinsic apoptosis as a mechanism of NTX-301 action. In conclusion, our data suggest that NTX-301 has more potent anti-leukemia activities compared to current HMA in clinic and synergizes with venetoclax in venetoclax-resistance and TP53-mutant AML and AML stem/progenitor cells, and warrants clinical evaluation

Expression of BFL-1 was shown to be upregulated in MYC+/BCL2+ double hit lymphoma cell lines treated with the BCL-2 inhibitor, Venetoclax, in vivo... First-in-class selective BFL-1 BH3 mimetics are shown to specifically inhibit cell growth of lymphoma cell lines in vitro and can induce efficacy in vivo in a BFL-1 overexpressing model. Further studies may be useful to determine whether compound A elicits anti-tumor efficacy in lymphoma alone or in combination with other anti-apoptotic agents.

Ven is FDA approved in combination with hypomethylating agents (HMA's) or low dose cytarabine for the treatment of de-novo AML in patients > 75 years or those ineligible for standard induction therapies...Additionally, cell derived xenograft (CDX) models of Ven-res showed significant reduction of pTyr-705 STAT3(~60%), total STAT3 (>90%) and MCL1 (~70%), on treatment with STAT3 degrader - KT-333 (currently in an early phase clinical trial:NCT05225584), as early as week 2 (Fig 1B). Our study suggests that targeting STAT3 and the downstream MCL1 represents a novel and effective strategy for Ven-resistant AML patients in clinic, with strong mechanistic rationales that can spur further clinical development of STAT3 degraders especially given the significant side effects of direct MCL1 inhibitors.

Given that the depletion of DDX19A/19B led to the mislocalization of polyadenylated mRNA and that neither the stability of the MCL1 protein nor the translation of MCL1 mRNA was affected by this depletion, as confirmed by RNA-FISH, and Actinomycin-D and Cycloheximide chase assays respectively, we concluded that DDX19A/19B are crucial for the nucleocytoplasmic transport of MCL1 mRNA. Mechanistically, the loss of DDX19A/19B leads to impaired cytoplasmic mRNA transport, leading to the inhibition of novel synthesis and reduced expression of MCL1 protein, thereby inducing intrinsic apoptosis. Furthermore, we found that DDX19A/19B depletion exerts synergistic effects with Selinexor through the downregulation of MCL1 expression, suggesting that DDX19A/19B levels could serve as a biomarker for Selinexor treatment in ALL.

Compared with the control, PPT reduced the expression of Mcl‑1 in both cell lines through a proteasome‑dependent protein degradation process. Overall, these results suggested that targeting of Mcl‑1 protein by PPT induced apoptosis, providing a foundation for further pre‑clinical and clinical study of its value in the management of OSCC.

We provide pre-clinical evidence that osimertinib is a promising candidate for the treatment of HCC via targeting tumor cells and angiogenesis. The combination of osimertinib and venetoclax is synergistic in inhibiting HCC.

Overall, these results suggest that high PL and high SRC plus high basal OXPHOS levels at disease onset, arguably with the concourse of MCL1/HK2 action, are significantly linked with shorter overall survival time in AML. Our data describe a new function for MCL1 protein in AMLs' cells: by forming a complex with HK2, MCL1 co-localizes to VDAC on the OMM, thus inducing glycolysis and OXPHOS, ultimately conferring metabolic plasticity and promoting resistance to therapy.

By the association of a deep transcriptomic characterization to conventional diagnostics, our analysis suggested novel mechanisms of resistance to VEN based combinations and detected the established ones. RTKs mutations are widespread within resistant patients, suggesting a potential therapy options. However, mutation in thispathway are redundant and not specific, thus hampering the selection of an appropriate target.

The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.

The venetoclax/INK128 regimen exerts significant anti-leukemic activity in various preclinical models through mechanisms involving MCL-1 down-regulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax resistant AML cells, and in in vivoAML models. Further investigation of this strategy appears warranted.

Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid-functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. In mice bearing MOLM-13-Luc or MV-411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid-functionalized smart nanodrugs hold remarkable potential for AML treatment.

Although HH inhibitor Glasdegib in combo with low-dose cytarabine achieved FDA approval for AML, Venetoclax (BCL-2 inhibitor/ABT-199) plus a hypomethylating agent (HMA) have been dominating the regimens in AML recently...Furthermore, ABT+Aza (Azacidine/HMA drug) induced more MCL-1 expression than ABT-199...GT1708 has been shown to reduce blast counts in three of 13 AML patients treated with higher doses and demonstrated favorite PK and safety profiles. In brief, these results support the clinical development of GT1708 in combination with ABT-199 in AML patients.

Furthermore, increases in human T cell viability, proliferation, and function as facilitated by AMG-176 could offer insight into the advancement of effector cell-based therapies, such as chimeric antigen receptor (CAR) therapy. We may employ AMG-176 alongside CAR T therapy in order to achieve more effective clinical outcomes.

Novel therapies for B lymphoblastic leukaemia such as blinatumomab and chimeric antigen receptor T-cell therapy are difficult to put into clinical use for T-ALL patients. Moreover, the underlying mechanism of MCL-1 downregulation upon HHT treatment in triggering apoptosis needs further exploration. Nevertheless, our study provides a solid ground work of establishing the role of HHT and its combination with venetoclax in treating T-ALL.Acknowledgements: The work was supported by Health and Medical Research Fund (Project No: 07182526).

We demonstrate that pan Bcl-2 family inhibition (ABT-263, rER: 1.52-1.56) or Bcl-xL specific inhibition (WEHI-539, A-1331852; rER: 1.31-2.00) radiosensitized wild-type PIK3CA/PTEN TNBC (MDA-MB-231, CAL-120) but failed to radiosensitize mutant PIK3CA/PTEN TNBC (rER: 0.90 - 1.07; MDA-MB-468, CAL-51, SUM-159). In vivo, ABT-263 or A-1331852 in combination with RT decreased tumor growth and increased tumor tripling time (p < 0.0001) in PIK3CA/PTEN wild-type TNBC cell line and patient-derived xenografts. Collectively, this study provides the preclinical rationale for early phase clinical trials testing the safety, tolerability, and efficacy of Bcl-xL inhibition and RT in women with wild-type PIK3CA/PTEN wild-type TNBC at high risk for recurrence.

FAM83D played a significant role in HCC progression by enhancing cell proliferation and migration and inhibiting apoptosis, which may have been caused by the inhibition of the FBXW7/MCL1 signaling pathway. Thus, FAM83D may be a promising therapeutic target for HCC.

To investigate the in vitro, ex vivo and in vivo effects of AZD5991 (AstraZeneca), a novel MCL1 inhibitor compound, alone or in combination with AZD4320 (BCL-2/BCL-XL inhibitor compound), venetoclax, cytarabine and doxorubicin. MCL1 overexpression in mononuclear cells from patients with acute leukemia and that present or not resistance to venetoclax treatment, is associated with poor prognosis and relapse disease. Our results demonstrated that co-targeting MCL-1, BCL-2 and BCL-xL, through the AZD5991 and AZD4320 compounds in the treatment of acute leukemias, may enhance therapeutic specificity, overcome chemoresistance and contribute with the cure of these aggressive malignant disorders.

The SUP-B15 IR line was also resistant to nilotinib, dasatinib, ponatinib and asciminib as well as showing resistance to venetoclax (LD50 = 74.94 nM vs 2.1 nM in the parental, p=0.0054) (Figure 1B)...While the SUP-B15 IR cell line was also resistant to the MCL-1-selective inhibitor S63845 alone (LD50=290 nM vs 78.5 nM for parental), combination therapy using S63845 with venetoclax overcame the resistance (CI=0.053 for 5 nM venetoclax and 50 nM S63845). Interestingly, combination treatment with imatinib and venetoclax (CI = 0.049 for 2 µM IM and 5 nM VEN) (Figure 1B) or asciminib and venetoclax (CI=0.032 for 2 µM asciminib and 5 nM venetoclax) also overcame resistance in SUP-B15 IR cells. Somatic mutations in PTPN11 in Ph+ ALL lead directly to TKI as well as venetoclax resistance rendering these mono-therapies ineffective. Combination therapy with TKIs plus venetoclax could be a promising treatment option for Ph+ ALL patients carrying PTPN11 mutations.

The combination also showed promising and synergistic antileukemic activity in vitro against AML cell lines with acquired resistance to the main chemotherapeutic drug AraC and primary AML cells derived from a patient at relapse post chemotherapy. The oncoprotein c-Myc represents a potential biomarker of AZD5991 sensitivity and inhibition of c-Myc synergistically enhances the antileukemic activity of AZD5991 against AML.

Furthermore, treatment with target compound in a 4T1 xenograft mouse model significantly suppressed the tumor growth. Overall, the small molecule described herein represents a promising Mcl-1 inhibitor for further study.

Conclusion Our data indicate that MBoIN could offer a new therapeutic strategy for tumours that overexpress MCL1. This novel mechanism of action would represent a new opportunity to avoid cardiotoxicity, one of the main drawbacks of current MCL1 inhibitors to reach the clinic.

Background: Resistance to AraC (cytarabine) is a major obstacle for effective treatment and limits survival rates of children with acute myeloid leukemia (AML). Our results demonstrate promising antileukemic activity of the combination of AZD4573 and Venetoclax against AraC-resistant AML cells. Future studies will determine the in vivo efficacy of this promising combination therapy against AraC-resistant xenograft NSGS mouse models.

Besides, overexpressed MCL1 also could reverse the enhancing effect of miR-432-5p on the paclitaxel sensitivity of CC cells. In conclusion, the present study showed that circ-CEP128 silencing could increase the paclitaxel sensitivity of CC by regulating the miR-432-5p/MCL1 axis.

Our data declared that MCL-1 inhibition alone or in combination with a chemotherapeutic agent is considered an appealing strategy for the induction of apoptosis in BCP-ALL cells.

This key metabolic hallmark of leukemia was recently reported as a feature of resistance to Cytarabine (AraC)-based therapy. Ongoing in vivo studies in AML PDX models will address the impact of ME-344 in the context of acquired AraC- and Bcl-2- resistance. In summary, our findings indicate ME-344 alone or in combination with Bcl-2 inhibition constitutes an important therapeutic modality that targets a unique metabolic vulnerability of AML.

Compared to ONO-7474 monotherapy, the combination of ONO- 7475/ABT-199 was even more potent in reducing leukemic burden and prolonging survival of mice in both model systems. These results suggest the ONO-7475/ABT-199 combination may be effective for acute myeloid leukemia therapy.

In lymphoma xenograft models, the combination of obinutuzumab and venetoclax causes more tumor growth inhibition compared to rituximab with venetoclax, possibly from more potent direct cytotoxicity. This trial design was reviewed and revised at ASH CRTI. Recruitment is ongoing and this trial is registered with ClinicalTrials.gov: NCT04722601.

The combination treatment of dTAG V -1 and venetoclax elicited a much stronger anti-leukemic effect compared to the treatment with only venetoclax or dTAG V -1, further highlighting MARCH5 as a promising synergistic target for enhancing the efficacy of venetoclax in AML. Taken together, our in vivo screening approach, coupled with CRISPR-competent PDX models and dTAG-directed protein degradation, constitute a useful platform for prioritizing AML targets emerging from in vitro screens to serve as the starting point for therapy development.

MiR-485-5p inhibitor or MCL1 overexpression (MCL1 OE) markedly restored the repressive effect of the si-LINC01224 pool on MCL1 expression level, as well as proliferation, migration, and invasion of HT29 and SW480 cells. This study identified LINC01224/miR-485-5p/MCL1 axis as a novel molecular therapeutic target involved in CC progression.

Overall, the complexity of MCL1 regulation and function represent challenges to the clinical application of MCL1 inhibitors. We now summarize the current knowledge regarding MCL1 structure, regulation, and function that could impact the clinical success of MCL1 inhibitors.

Interestingly, when overexpressed, Mcl-1 and Bok interact physically and functionally, in a manner that depends upon the transmembrane domain of Bok. Overall, this work shows that the Bok interactome is different from those of Mcl-1 and Bak, identifies novel proximities and potential interaction points for Bcl-2 family members, and suggests that Bok may regulate mitochondrial fission via Mcl-1 and Drp1.

Results In comparison to parental, the SUP-B15 IR, DR and PR cell lines were resistant to all TKIs (imatinib, nilotinib, dasatinib and ponatinib) and to asciminib...Whilst these cell lines were resistant to the Mcl-1‐selective inhibitor S63845 (LD50=290 nM vs 78.5 nM for parental), combination therapy with venetoclax was synergistic in overcoming resistance (CI=0.051 for 50 nM S63845 and 5 nM venetoclax)...The DRKRASmut and PRNRASmut lines instead showed overexpression of Bcl-2 (P=0.0079 and P=0.01 respectively), but not pBCR-ABL or Mcl-1, which could explain why venetoclax alone overcame resistance in these cell lines Conclusion Combination therapy of TKIs and venetoclax could be promising for Ph+ ALL patients carrying PTPN11 mutations and Mcl-1 overexpression. Studies are ongoing to determine the role of the mutations in PTPN11 in the development of the resistance.

Additionally, the multinucleated cells underwent apoptotic cell death in a cell context‑dependent manner, which was associated with the reduction of Mcl‑1 protein levels. Findings of the present study indicate that EEJS could be effective for treating human oral cancer by promoting mitotic catastrophe linked to apoptotic cell death.

The SKMM2 MM cell line, harboring t(11;14), del(CYLD) was highly sensitive to Venetoclax...Of note, these latter resulted sensitive to Sabutoclax, a panBCL2-axis inhibitor... Our study showed a link between the genomic archi- tecture and transcriptome in MM, where CNAs and CRs had a stron- ger impact on expression than gene mutations. Within these lattes UPON GENOMIC HS ones need further testing as they may represent future treatment targets. Moreover, the mutational status is crucial since, due to the transcriptomic consequences of bi-allelic events which provides bio- logical basis for the observed prognostic impact of “double-hit” MM.

Our previous work demonstrated that a novel dual inhibitor of PI3K and HDAC, CUDC-907, synergizes with venetoclax by overcoming these resistance mechanisms in bulk AML cells and suppressing c-Myc expression and mTOR activity. Finally we will confirm that these two drugs when combined, reduce the number of LSCs in primary patient samples with a PDX model and flow cytometry for known LSC markers, CD38, CD34 & CD123. The results of this study will form a solid foundation for the clinical evaluation of this promising combination therapy for the treatment of AML and potentially reduce the incidence of relapse.

Combined kinase and phosphatase inhibition experiments suggest that the MCL-1 half-life in MM is regulated by the counteracting functions of JNK and PP2A. These findings increase the understanding of the mechanisms by which MCL-1 is post-translationally regulated, which may provide novel strategies to inhibit MCL-1 in MM cells.