Understanding how cells respond to cancer treatment drugs is key for developing effective therapies. Recent research led by AbbVie scientists has introduced innovative methods to evaluate cellular drug sensitivity more comprehensively. By combining drug-induced growth rate inhibition analysis with intracellular drug exposure measurements, the study aims to bridge the gap between what researchers measure outside of cells and what really happens inside.
The primary focus of this research was on the challenges often faced during drug discovery processes, particularly the disconnect between extracellular drug concentrations and the actual concentrations at the intracellular sites necessary for achieving desired pharmacological effects. This gap is frequently cited as one of the principal reasons for the failure of drug candidates during preclinical evaluations, leading to discouraging attrition rates.
The researchers utilized growth rate inhibition (GR) methods, which quantify drug sensitivity per cell division, as opposed to traditional metrics like IC50. This new approach allows for more accurate measurement of cellular responses by normalizing growth inhibition data during experimentation. They analyzed two specific microtubule inhibitors from the auristatin family, monomethyl auristatin E (MMAE) and monomethyl auristatin D (MMAD), to determine their effectiveness against various triple-negative breast cancer (TNBC) cell lines and liver sinusoidal endothelial cells (LSECs).
According to the study, "The inability to achieve adequate drug exposure at the target site of action is one of the primary reasons for attrition during preclinical drug discovery work and ultimate failure in the clinic." Through their innovative methodology, the researchers aimed to not only understand the degree of sensitivity across different cell types but also to ascertain the intracellular concentrations of drugs required for effective growth inhibition.
Utilizing advanced liquid chromatography-tandem mass spectrometry (LC-MS/MS), the researchers were able to obtain quantitative measures of drug concentrations inside the cells—a step they noted is pivotal for correlational evaluations between drug exposure and therapeutic response.
The findings revealed significant differences between the cellular responses to MMAE and MMAD. For example, cells exhibiting resistance to typical treatments could still be impacted by these auristatins. The study showed varying growth inhibition metrics across different cell lines, illustrating the differential sensitivity and underlining the complexity of measuring drug responses. The GR analysis demonstrated defined GR50 values for the sensitive MDA-MB-468 and HCC1806 cell lines, whereas the resistant HCC1143 and HCC1937 lines exhibited marginal growth inhibition.
Researchers emphasized, "GR methods quantify drug sensitivity on a per cell division basis," showcasing the robustness of their approach. The study concluded with the assertion of the importance of utilizing intracellular measurements for calculating therapeutic indices, claiming, "Using intracellular measurements for calculating therapeutic index provides added benefit over using drug sensitivity only." This distinction highlights the necessity of coupling extracellular measurements with intracellular methods to create more accurate predictions for drug effectiveness.
Overall, the study's innovations present promising tools for enhancing the efficiency of drug development, particularly for cancer treatment, and provide insights necessary for improving the therapeutic index of drug candidates. By refining how drug potency and sensitivity are assessed, these methods pave the way for more targeted and effective therapies against cancer.