Abstract
Cancer drug resistance presents a challenge for precision medicine. Drug-resistant mutations are always emerging. In this study, we explored the relationship between drug-resistant mutations and drug resistance from the perspective of protein structure. By combining data from previously identified drug-resistant mutations and information of protein structure and function, we used machine learning-based methods to build models to predict cancer drug resistance mutations. The performance of our combined model achieved an accuracy of 86%, a Matthews correlation coefficient score of 0.57, and an F1 score of 0.66. We have constructed a fast, reliable method that predicts and investigates cancer drug resistance in a protein structure. Nonetheless, more information is needed concerning drug resistance and, in particular, clarification is needed about the relationships between the drug and the drug resistance mutations in proteins. Highly accurate predictions regarding drug resistance mutations can be helpful for developing new strategies with personalized cancer treatments. Our novel concept, which combines protein structure information, has the potential to elucidate physiological mechanisms of cancer drug resistance.
Highlights
One of the greatest challenges of this century is precision medicine, highlighted by the search for personalized cancer medicine
A problem with targeted drug therapy is the emergence of cancer drug resistance [2], as with chemotherapy [3,4]
We explored the relationship between resistance mutations and cancer drug resistance from the perspective of protein structures and we built a reliable prediction model to distinguish which mutation(s) might be responsible for drug resistance
Summary
One of the greatest challenges of this century is precision medicine, highlighted by the search for personalized cancer medicine. In recent decades, targeted cancer therapy has been associated with significant improvements in survival rates, so has become one of the standard strategies for cancer treatment [1]. A problem with targeted drug therapy is the emergence of cancer drug resistance [2], as with chemotherapy [3,4]. Many studies have investigated the mechanisms of resistance to chemotherapy and their solutions [5,6,7,8,9,10,11,12,13,14]. The mechanisms of how cancer cells acquire targeted drug resistance are not clarified. Some patients develop resistance to targeted drug therapy post-treatment, possibly due to the occurrence of drug-resistant mutations [15].
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