Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts.

In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML. SIGNIFICANCE: Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.

Physicochemical Significance of Topological Indices: Importance in Drug Discovery Research.

BACKGROUND: Quantitative Structure-Activity Relationship (QSAR) studies describing the correlations between biological activity as dependent parameters and physicochemical and structural descriptors, including topological indices (TIs) as independent parameters, play an important role in drug discovery research. The emergence of graph theory in exploring the structural attributes of the chemical space has led to the evolution of various TIs, which have made their way into drug discovery. The TIs are easy to compute compared to the empirical parameters, but they lack physiochemical interpretation, which is essential in understanding the mechanism of action. OBJECTIVES: Hence, efforts have been made to review the work on the advances in topological indices, their physicochemical significance, and their role in developing QSAR models. METHODS: A literature search has been carried out, and the research article providing evidence of the physicochemical significance of the topological parameters as well as some recent studies utilizing these parameters in the development of QSAR models, have been evaluated. RESULT: In this review, the physicochemical significance of TIs have been described through their correlations between empirical parameters in terms of explainable physicochemical properties, along with their application in the development of predictive QSAR models. CONCLUSION: Most of these findings suggest a common trend of TIs correlation with MR rather than logP or other parameters; nevertheless, the developed models may be useful in both drug and vaccine development.