Understanding Drug Sensitivity and Tackling Resistance in Cancer

Abstract

Decades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the well-documented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immune-suppressive features and immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe a framework to understand the types and biological causes of resistance, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.

L’embryon de poule

“…Les tumeurs sont des écosystèmes complexes dans lesquels les cellules cancéreuses établissent un dialogue dynamique avec leur microenvironnement constitué de matrice extracellulaire et de plusieurs types de cellules, dont les cellules stromales et les cellules immunitaires [21]. Ce microenvironnement tumoral complexe module la croissance de la tumeur et sa réponse aux drogues anti-tumorales [22]. Une des limitations majeures des modèles de xénogreffe chez la souris immunodéprimée est la difficulté de tester l'effet d'immunomodulateurs ou d'inhibiteurs de points de contrôle immunitaire.…”

The GlycosylatedN-Terminal Domain of MUC1 Is Involved in Chemoresistance by Modulating Drug Permeation Across the Plasma Membrane

“…The development of chemoresistance is a critical problem in cancer chemotherapy. Despite the current progress of radiotherapy and immunotherapy, cancer chemotherapy remains the primary option for the treatment of patients with unresectable tumors (Holohan et al, 2013;Tyner et al, 2022).…”

“…Chemoresistance could be either inherent due to genetic characteristics or acquired due to exposure to anticancer drugs. In the latter case, multidrug resistance causes a serious problem in chemotherapy, as cancer cells become resistant to structurally and functionally unrelated drugs upon single drug treatment (Wang et al, 2010;Tyner et al, 2022). The underlying mechanisms of multidrug resistance involve increased drug efflux (Tyner et al, 2022), activation of drug metabolism (Meijer et al, 1992), drug target mutation (Kobayashi et al, 2009;Adashek et al, 2021), DNA damage repair (Furuta et al, 2002;Zimmermann et al, 2022), and inhibition of apoptosis (Montero and Haq, 2022).…”

“…In the latter case, multidrug resistance causes a serious problem in chemotherapy, as cancer cells become resistant to structurally and functionally unrelated drugs upon single drug treatment (Wang et al, 2010;Tyner et al, 2022). The underlying mechanisms of multidrug resistance involve increased drug efflux (Tyner et al, 2022), activation of drug metabolism (Meijer et al, 1992), drug target mutation (Kobayashi et al, 2009;Adashek et al, 2021), DNA damage repair (Furuta et al, 2002;Zimmermann et al, 2022), and inhibition of apoptosis (Montero and Haq, 2022). It is well-known that ATP-driven efflux transporters, such as ABCB1/P-gp, ABCG2/BCRP, and ABCCs/MRPs, are clinically relevant to multidrug resistance by reducing the intracellular accumulation of anticancer drugs (Tyner et al, 2022).…”

“…The underlying mechanisms of multidrug resistance involve increased drug efflux (Tyner et al, 2022), activation of drug metabolism (Meijer et al, 1992), drug target mutation (Kobayashi et al, 2009;Adashek et al, 2021), DNA damage repair (Furuta et al, 2002;Zimmermann et al, 2022), and inhibition of apoptosis (Montero and Haq, 2022). It is well-known that ATP-driven efflux transporters, such as ABCB1/P-gp, ABCG2/BCRP, and ABCCs/MRPs, are clinically relevant to multidrug resistance by reducing the intracellular accumulation of anticancer drugs (Tyner et al, 2022). Therefore, membrane transport and the subsequent accumulation of anticancer drugs in cancer cells are suggested to be pivotal for successful cancer chemotherapy.…”