Drug-Resistant Cancer Treatment Strategies Based on the Dynamics of Clonal Evolution and PKPD Modeling of Drug Combinations

Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma

“…However, increasing evidence suggests that treatments aimed at eliminating susceptible subpopulations result in altered tumor microenvironment favoring resistant subpopulations, which enhances the probability and rate of resistance emergence ( Chatterjee and Bivona, 2019 ). Increasing research has focused on dose strategies to combat resistance in tumor progression in combination therapy, and both extremes of too high and too low doses may unnecessarily accelerate the spread of resistance ( Kouyos et al, 2014 ; Vakil and Trappe, 2022 ). Some results suggest that maintaining a low-dose treatment strategy is advantageous when the size of the patient‘s tumor is tolerable, as it allows the susceptible clonal population to survive and compete with the resistant subpopulation to prevent the resistant population from propagating uncontrollably and taking over the entire tumor, thus having more feared consequences for the patient ( Vakil and Trappe, 2021 ).…”

Dosage strategies for delaying resistance emergence in heterogeneous tumors

“…In this section, we provide a quantitative formulation and mathematical framework that models the effect of drugs on the clonal evolution of competing cells, and the impact of therapeutics on delaying the emergence of resistance during the control phase. Table 2 contains the baseline values of the input parameters assumed in this evaluation which are mainly extracted from [4,13,21]. The table also shows the range of the parameters that will be used in the sensitivity analysis of the model.…”

“…In this paper, it is assumed that that an aggressive treatment has been applied to reduce the size of tumor to a tolerable burden with a rationale similar to the method proposed in [4]. Then, in the control phase of the treatment, a containment strategy is followed to delay resistance emergence.…”

“…While using maximum tolerated dose (MTD) is thought to achieve maximum therapeutic benefit by killing a large number of cancerous cells, there is increasing evidence that undermines this approach and the basis for its application [3]. The authors in [4] propose an optimization problem for determining a dosage strategy in combination therapy to combat drug resistance in tumor progression. The authors in [3] introduce a submaximal therapeutic protocol that is designed based on the complex trade‐offs between the death of cancerous cells, the emergence of resistance, and metastases.…”