Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21

Prabaharan, Chandra B.; Yang, Allan Boyao; Chidambaram, Divya; Rajamanickam, Karthic; Napper, Scott; Sakharkar, Meena Kishore

doi:10.1007/s10637-019-00837-w

Cited by 9 publications

(8 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to recent studies, STAT3 has a crucial role in Her2 + cell apoptosis resistance. 22,23 Lo et al have demonstrated that STAT3 inhibition can reduce Her2 + cell growth and have introduced it as a potential target in triple-negative breast cancers without effective treatments. 24 One of the Herceptin complications is the activation of AKT and PI3K, leading to apoptosis resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Tumour cell apoptosis is a sophisticated process that relies on many factors. According to recent studies, STAT3 has a crucial role in Her2 + cell apoptosis resistance 22,23 . Lo et al have demonstrated that STAT3 inhibition can reduce Her2 + cell growth and have introduced it as a potential target in triple‐negative breast cancers without effective treatments 24 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti‐breast cancer immunity: An in vitro study

et al. 2023

View full text Add to dashboard Cite

Breast cancer (BC) is the most prevalent diagnosed cancer among women. Herceptin blocks the effects of Her‐2 and tumour cell growth. Despite many achievements using Herceptin in Her‐2+ invasive BC treatment, there are treatment failures and resistances. The signal transducer and activator of transcription 3 (STAT3) is persistently activated in BC and is associated with immune suppression and tumour cell proliferation. We evaluated whether STAT3 inhibition could increase Herceptin impact on in vitro reduction of immune checkpoint inhibitors and polarize T cells to a protective immune response. We treated SK‐BR‐3 cells with Herceptin and the STAT3‐inhibitor (FLLL32) and assessed the apoptosis and expression of apoptosis‐related proteins, VEGF, Her‐2 and apoptosis targets of STAT3. PBMCs were isolated from healthy donors and co‐cultured with SK‐BR‐3 cells in the presence or absence of Herceptin and FLLL32. PD‐L1, CTLA‐4, TIM‐3 and T‐cell intracellular cytokines were then evaluated. Our results demonstrated that STAT3 inhibition and Herceptin increased SK‐BR‐3 cell apoptosis, significantly. STAT3 inhibition through combination treatment had a more significant effect on regulating PD‐1, TIM‐3 and CTLA‐4 expression on PBMCs. Alternatively, the combination of FLLL32 and Herceptin promoted T helper‐1 protective immune response. The combination of FLLL32 and Herceptin suppress the expression of immune checkpoints and provoke the T‐helper1 immune response in lymphocytes. Our analysis indicates STAT3 as a promising target that improves Herceptin's role in breast cancer cell apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti‐breast cancer immunity: An in vitro study

et al. 2023

View full text Add to dashboard Cite

show abstract

“…A potential cause of decreased PARP1 serum expression could be a result of tumor reduction upon treatment, which needs to be further investigated. Ibrutinib that is included in the treatment is known to activate caspase signaling that in the next step causes PARP1 cleavage, a known hallmark of cell death through apoptosis 28–33 . In this study, the antibody‐fragment used targeting PARP1 is directed to the C‐terminal part of the protein and will thus detect either the full protein or the 89 kDa caspase‐cleaved subunit, both including the C‐terminal domain.…”

Section: Discussionmentioning

confidence: 99%

Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma

et al. 2021

View full text Add to dashboard Cite

Background: The possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies. Aim: To pin-point biologically relevant changes in pre-and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients. Methods: Pre-and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points. Results: Proteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-β1, CD40 and complement component 4 comparing pre-and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS). Conclusion: We show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response.

show abstract

“…Ibrutinib has shown antitumour effects on chronic lymphocytic leukaemia [20][21][22][23]. Ibrutinib also inhibited growth in solid cancers, but the results were limited [24][25][26][27]. Based on these findings, a series of derivatives were developed.…”

Section: Discussionmentioning

confidence: 99%

The Ibr-7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p-EGFR

et al. 2020

View full text Add to dashboard Cite

Background Radiotherapy is one of the main treatments for pancreatic cancer, but radiation resistance limits its clinical application. As a result, novel therapeutic agents to improve radiosensitivity are urgently needed. This study aimed to investigate the effect of Ibr-7 (a derivative of ibrutinib) on the radiosensitivity of human pancreatic cancer cells. Methods The effect of Ibr-7 on pancreatic cancer cell proliferation was detected by CCK-8 assays. Radiosensitivity was assessed by clonogenic formation assays. Cell cycle and cell apoptosis were analysed by flow cytometry. DNA damage was evaluated by immunofluorescence analysis. The expression levels of PARP, Cleaved caspase 3, p-EGFR and EGFR were determined by western blot. Results Ibr-7 showed an anti-proliferative effect on PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 μmol/L) enhanced the effect of radiation on PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or in combination with radiation. Overexpression of p-EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in the Ibr-7 plus radiation group. Conclusions Our study indicated the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells.

show abstract

Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21

Cited by 9 publications

References 53 publications

Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti‐breast cancer immunity: An in vitro study

Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti‐breast cancer immunity: An in vitro study

Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma

The Ibr-7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p-EGFR

Contact Info

Product

Resources

About