The efficiency of tyrosine kinase inhibitors (TKIs) displays substantial interpatient variability in non-small cell lung cancer (NSCLC), even though patients receive the same targeted therapy. This observation raises the question on how resistance to TKI therapy arises and whether treatment resistance can be predicted.
In this thesis of Weiting Li we explored some of these challenges by studying on- and off-target resistance mutations. We determined presence of pre-existing resistant minor subclones in EGFR and ALK driven NSCLC. Using the highly sensitive digital droplet PCR approach, we analyzed low-abundant resistance-associated mutations in samples obtained prior to therapy. Minor resistant clones were detected only in a small subset of the cases, indicating that most on-target resistance mutations are treatment induced or below the detection limit. Moreover, for the ALK study we observed treatment associated resistance mutations exclusively in cases where the pre- and post-treatment sample were obtained from the same organ. Off-target resistance mechanisms contributing to failure of BRAF/MEK inhibition are not yet well characterized. We explored resistance mechanism in BRAF-mutant NSCLC using whole exome sequencing. Several post-treatment specific mutations were identified in pathways previously associated with resistance to BRAF/MEK inhibition, suggesting both known and novel mechanisms may contribute to therapeutic failure in this patient subgroup. Finally, we explored feasibility of utilizing short-term ex vivo cultures from pleural effusion-derived tumor cells for in vitro drug sensitivity testing.
This strategy represents a promising option to guide personalized treatment selection, although challenges remain regarding culture success rates and cellular heterogeneity.
