scholarly journals Trials to Overcome Drug Resistance to EGFR and ALK Targeted Therapies – Past, Present, and Future

2014 ◽  
Vol 4 ◽  
Author(s):  
Johanna N. Spaans ◽  
Glenwood D. Goss
Keyword(s):  
Drug Resistance ◽  
Targeted Therapies

scholarly journals Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1292 ◽  
Author(s):  
Shirin Hafezi ◽  
Mohamed Rahmani
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Targeted Therapies ◽  
Single Agent ◽  
Therapeutic Agents ◽  
Malignant Cells ◽  
Future Perspectives ◽  
Comprehensive Overview ◽  
Antiapoptotic Proteins ◽  
Preclinical And Clinical Studies

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.

scholarly journals Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

2019 ◽  
Vol 39 (S1) ◽  
pp. 43-62 ◽  
Author(s):  
Laura Fouassier ◽  
Marco Marzioni ◽  
Marta B. Afonso ◽  
Steven Dooley ◽  
Kevin Gaston ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Targeted Therapies ◽  
Molecular Pathogenesis

scholarly journals A Compendium of Information on the Lysosome

2021 ◽  
Vol 9 ◽  
Author(s):  
Nadia Bouhamdani ◽  
Dominique Comeau ◽  
Sandra Turcotte
Keyword(s):  
Drug Resistance ◽  
Scientific Knowledge ◽  
Targeted Therapies ◽  
Cancer Drug ◽  
Functional Changes ◽  
The Past ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Long Time ◽  
Signaling Organelles

For a long time, lysosomes were considered as mere waste bags for cellular constituents. Thankfully, studies carried out in the past 15 years were brimming with elegant and crucial breakthroughs in lysosome research, uncovering their complex roles as nutrient sensors and characterizing them as crucial multifaceted signaling organelles. This review presents the scientific knowledge on lysosome physiology and functions, starting with their discovery and reviewing up to date ground-breaking discoveries highlighting their heterogeneous functions as well as pending questions that remain to be answered. We also review the roles of lysosomes in anti-cancer drug resistance and how they undergo a series of molecular and functional changes during malignant transformation which lead to tumor aggression, angiogenesis, and metastases. Finally, we discuss the strategy of targeting lysosomes in cancer which could lead to the development of new and effective targeted therapies.

scholarly journals Dissecting targeted therapy resistance: Integrating models to quantify environment mediated drug resistance

2017 ◽  
Author(s):  
Noemi Picco ◽  
Erik Sahai ◽  
Philip K. Maini ◽  
Alexander R. A. Anderson
Keyword(s):  
Drug Resistance ◽  
Targeted Therapy ◽  
Targeted Therapies ◽  
Carrying Capacity ◽  
Conflicts Of Interest ◽  
Treatment Strategies ◽  
Model Systems ◽  
Significant Heterogeneity

AbstractDrug resistance is the single most important driver of cancer treatment failure for modern targeted therapies. This resistance may be due to the presence of dormant or aggressive tumor cell phenotypes or to context-driven protection. Non-malignant cells and other factors, constituting the microenvironment in which the tumor grows (the stroma), are now thought to play a crucial role in both therapeutic response and resistance. Specifically, the dialogue between the tumor and stroma has been shown to modulate the response to molecularly targeted therapies, through proliferative and survival signaling. The goal of this work is to investigate interactions between a growing tumor and its surrounding stroma in facilitating the emergence of drug resistance. We use mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating the intrinsic and extrinsic components of resistance in BRAF mutated melanoma. The model describes tumor-stroma dynamics both with and without treatment. Calibration of our model, through the integration of experimental data, revealed significant variation across animal replicates in either the intensity of stromal promotion or intrinsic tissue carrying capacity. Furthermore our study highlights the need to account for this variation in the design of treatment strategies. Major Findings. Through the integration of a simple mathematical model with in vitro and in vivo experimental growth dynamics of melanoma cell lines (both with and without drug), we were able to dissect the relative contributions of intrinsic versus environmental resistance. Our study revealed significant heterogeneity in vivo, indicating that there is a diversity of either stromal promotion or tumor carrying capacity under targeted therapy. We believe this variation may be one possible explanation for the heterogeneity observed across patients and within individual patients with multiple metastases. Therefore, quantifying this variation both within in vivo model systems and in individual patients could have a significant impact on the design of future treatment strategies that target both the tumor and stroma. Further, we present guidelines for building more effective and longer lasting therapeutic strategies utilizing our experimentally calibrated model. These strategies explicitly consider the protective nature of the stroma and utilize inhibitors that modulate it.PrecisQuantification of the environmental contribution to drug resistance reveals heterogeneity that significantly alters treatment dynamics that can be exploited for therapeutic gain.Financial SupportPicco and Anderson: US National Cancer Institute grant U01CA151924.Picco: UK Engineering and Physical Sciences Research Council (EPSRC grant number EP/G037280/1).Conflict of Interest DisclosureThe authors declare no potential conflicts of interest.

scholarly journals APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

2021 ◽  
Author(s):  
Hideko Isozaki ◽  
Ammal Abbasi ◽  
Naveed Nikpour ◽  
Adam Langenbucher ◽  
Wenjia Su ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Targeted Therapies ◽  
Acquired Resistance ◽  
Small Cell ◽  
Tumor Evolution ◽  
Small Cell Lung ◽  
Acquired Drug Resistance

AbstractAcquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

MicroRNAs as a drug resistance mechanism to targeted therapies in EGFR-mutated NSCLC: Current implications and future directions

2019 ◽  
Vol 42 ◽  
pp. 1-11 ◽  
Author(s):  
Alessandro Leonetti ◽  
Yehuda G. Assaraf ◽  
Paraskevi D. Veltsista ◽  
Btissame El Hassouni ◽  
Marcello Tiseo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Targeted Therapies ◽  
Resistance Mechanism ◽  
Future Directions ◽  
Egfr Mutated

scholarly journals Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2666
Author(s):  
Heidie Frisco Cabanos ◽  
Aaron N. Hata
Keyword(s):  
Drug Resistance ◽  
Cancer Patients ◽  
Targeted Therapies ◽  
Residual Disease ◽  
Critical Role ◽  
Persister Cells ◽  
Continuous Therapy ◽  
Acquired Drug Resistance ◽  
Slow Cycling ◽  
Minimal Residual

Drug resistance is perhaps the greatest challenge in improving outcomes for cancer patients undergoing treatment with targeted therapies. It is becoming clear that “persisters,” a subpopulation of drug-tolerant cells found in cancer populations, play a critical role in the development of drug resistance. Persisters are able to maintain viability under therapy but are typically slow cycling or dormant. These cells do not harbor classic drug resistance driver alterations, and their partial resistance phenotype is transient and reversible upon removal of the drug. In the clinic, the persister state most closely corresponds to minimal residual disease from which relapse can occur if treatment is discontinued or if acquired drug resistance develops in response to continuous therapy. Thus, eliminating persister cells will be crucial to improve outcomes for cancer patients. Using lung cancer targeted therapies as a primary paradigm, this review will give an overview of the characteristics of drug-tolerant persister cells, mechanisms associated with drug tolerance, and potential therapeutic opportunities to target this persister cell population in tumors.

scholarly journals Nano-Based Drug Delivery and Targeting to Overcome Drug Resistance of Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5480
Author(s):  
Melayshia McFadden ◽  
Santosh Kumar Singh ◽  
Gabriela Oprea-Ilies ◽  
Rajesh Singh
Keyword(s):  
Drug Resistance ◽  
Natural Products ◽  
Targeted Therapies ◽  
Drug Targets ◽  
Direct Access ◽  
High Morbidity ◽  
Drug Induced ◽  
Specific Tumor ◽  
Platinum Based Chemotherapy ◽  
Anti Cancer

Ovarian cancer (OvCa) is a destructive malignancy due to difficulties in early detection and late advanced-stage diagnoses, leading to high morbidity and mortality rates for women. Currently, the quality treatment for OvCa includes tumor debulking surgery and intravenous platinum-based chemotherapy. However, numerous patients either succumb to the disease or undergo relapse due to drug resistance, such as to platinum drugs. There are several mechanisms that cause cancer cells’ resistance to chemotherapy, such as inactivation of the drug, alteration of the drug targets, enhancement of DNA repair of drug-induced damage, and multidrug resistance (MDR). Some targeted therapies, such as nanoparticles, and some non-targeted therapies, such as natural products, reverse MDR. Nanoparticle targeting can lead to the reversal of MDR by allowing direct access for agents to specific tumor sites. Natural products have many anti-cancer properties that adversely regulate the factors contributing to MDR. The present review displays the current problems in OvCa treatments that lead to resistance and proposes using nanotechnology and natural products to overcome drug resistance.

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