Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer – A comprehensive review from chemotherapy to immunotherapy

Kaboli, Parham Jabbarzadeh; Salimian, Fatemeh; Aghapour, Sevil; Xiang, Shixin; Zhao, Qijie; Li, Mingxing; Wu, Xu; Du, Fukuan; Zhao, Yueshui; Shen, Jing; Cho, Chi Hin; Xiao, Zhangang

doi:10.1016/j.phrs.2020.104806

Cited by 102 publications

(60 citation statements)

References 185 publications

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“…DSF/Cu 2+ also inhibited T cell infiltration while failed to hamper HCC tumor growth [ 248 ]. The Akt inhibitors ipatasertib, capivasertib, uprosertib, and MK-2206 inhibit PD-L1 expression in breast cancer [ 249 ]. Trastuzumab deruxtecan (DS-8201a), a HER2-targeting drug, enhanced PD-L1 expression and CD8+ T cell infiltration in breast cancer, which DS-8201a also had synergistic effect with anti-PD-1 therapy [ 250 ].…”

Section: Potential Drug Intervention On Pd-l1 and Ctla-4mentioning

confidence: 99%

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Zhang

Dai

et al. 2021

J Exp Clin Cancer Res

293

168

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The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.

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Section: Potential Drug Intervention On Pd-l1 and Ctla-4mentioning

confidence: 99%

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Zhang

Dai

et al. 2021

J Exp Clin Cancer Res

293

168

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“…Many recent studies suggest that EMT and CSC are intimately interconnected and their involvements in [11,70,146] . One possible mechanism is that the activation of EMT and induction of CSC during tumor development are associated with activation of numerous signaling pathways that control CSC functions including self-renewal, differentiation, survival and metastatic potential.…”

Section: Pathways Connnecting Emt and Csc And The Implication In Drug Resistancementioning

confidence: 99%

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

Zhang¹,

Steed²,

Co³

et al. 2021

CDR

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The cancer stem cell (CSC) state and epithelial-mesenchymal transition (EMT) activation are tightly interconnected. Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness, enhanced drug transporters, anti-apoptotic machinery and DNA repair system. Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance. ATP, particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization, induces and regulates EMT and CSC. The three of them work together to enhance drug resistance. New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.

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“…In the neoadjuvant setting, the phase II FAIRLANE study (NCT02301988), evaluating Paclitaxel plus Ipatasertib or placebo in TNBC, partially supports the potential utility as biomarker for the PIK3CA/AKT1/PTEN alterations; there was, indeed, in the trial, a numerically but non-significant increase in pCR rates, with more pronounced results in patients with PTEN-low tumors (32% versus 6%) and PIK3CA/AKT1/PTEN -altered tumors (39% versus 9%) [ 169 ]. In contrast, in the phase Ib study NCT03800836, evaluating the efficacy and safety of the combination of Ipatasertib, Tecentriq (Atezolizumab), and chemotherapy (Paclitaxel or Nab-paclitaxel) as a first-line treatment option for people with advanced TNBC, the objective response rate (ORR) was 73% (95% CI 53–88%), irrespective of tumor biomarker status [ 170 , 171 ]. A confirmatory phase III study NCT04177108 investigating the combination of ipatasertib, atezolizumab and paclitaxel as first-line therapy for locally advanced/metastatic TNBC cancer is still ongoing.…”

Section: Pi3kca and Pten Mutations As Predictive Biomarkersmentioning

confidence: 99%

Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives

Cocco

Piezzo

Calabrese

et al. 2020

IJMS

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Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors characterized by aggressive behavior, high risk of distant recurrence, and poor survival. Chemotherapy is still the main therapeutic approach for this subgroup of patients, therefore, progress in the treatment of TNBC remains an important challenge. Data derived from molecular technologies have identified TNBCs with different gene expression and mutation profiles that may help developing targeted therapies. So far, however, only a few of these have shown to improve the prognosis and outcomes of TNBC patients. Robust predictive biomarkers to accelerate clinical progress are needed. Herein, we review prognostic and predictive biomarkers in TNBC, discuss the current evidence supporting their use, and look at the future of this research field.

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Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer – A comprehensive review from chemotherapy to immunotherapy

Cited by 102 publications

References 185 publications

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives

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