Over the past 10 years, the chemotherapeutic arsenal has been expanded to include molecular-targeted therapies based on the principle that cancer cells become addicted to a single driver oncogene. This therapeutic approach not only enables healthy cells to be spared, and hence limits toxicities, but it also, and perhaps more importantly, brings the median survival from about 10 months with conventional treatment to more than 30 months when integrating targeted agents in certain metastatic cancers.
Unfortunately, most tumours are capable of adapting to the treatment, thereby limiting the clinical benefit of these new targeted therapies. The extensive examination of the resistant tumours has enabled to elucidate three main categories of resistance:
- The first category is the acquisition of a secondary mutation within the kinase domain of the target. The mutation often leads to a steric class with the inhibitor binding but the ATP can still fit within the active site. Therefore, the downstream prosurvival and proliferative pathways remain activated.
- The second category is the activation of bypass kinases. In such case, the target is inhibited by the drug but other kinases become overactivated to compensate for this inhibition and maintain the activation of the downstream pathways.
- Finally in a third category, the target and the downstream kinases are inhibited but the cells fail to undergo apoptosis. The resistance mechanisms in such cases are less clear but epigenetic mechanism is highly suspected.
To identify a broad spectrum of resistance mechanisms, that are highly clinically relevant, the researchers establish new laboratory models of resistance directly from patient biopsies. This project is connected to the clinical trial "MATCH-R" (for “matching resistance”) sponsored by the institution of the author of this new V-Learning module, allowing collection of repeated biopsies before and after resistance in patients receiving targeted therapies.
In this module, after a brief introduction on tyrosine kinase inhibitors and an overview of general resistance mechanisms, the author presents specific examples of actionable drivers in lung adenocarcinoma and other tumour types and discusses the future challenges in precision medicine.
