Abstract
Single cells demonstrate additional driver alterations along with initial EGFR mutations to drive resistance.
Major Finding: Single cells demonstrate additional driver alterations along with initial EGFR mutations to drive resistance.
Concept: Patient-derived cells were used for pharmacologic evaluation targeting both molecular drivers.
Impact: This work suggests that simultaneous inhibition of both drivers can lead to effective clinical benefit.
Tyrosine kinase inhibitors (TKI), especially those targeting EGFR, have improved outcomes for non–small cell lung cancer (NSCLC), but additional mutations drive acquired resistance to these therapies. The T790M mutation, an EGFR activating mutation, attributes resistance to first- and second-generation TKIs, with the third-generation TKI osimertinib inhibiting T790M mutations and demonstrating improved progression-free survival and overall survival compared with earlier generation TKIs. Despite this, resistance to osimertinib still occurs; however, whether the mechanisms behind this arise in a single cancer cell or in distinct cancer cell populations continues to be incompletely understood. Chen and colleagues used single-cell next-generation sequencing on frozen tissue from 45 patients with NSCLC who progressed on osimertinib while enrolled in the MATCH-R trial. Additional alterations that were identified in these patients included tertiary EGFR mutations as well as mutations in bypass pathway activation including MET, KRAS, PTEN, or PIK3CA, with these generally being mutually exclusive with one another. Secondary oncogenic alterations occurred in 20% of studied cases and included KIF5B–RET, STRN–ALK, FGFR–TACC3 fusions as well as mutations in BRAF and KRAS, with their lack of detection in matched pre-osimertinib samples indicating their emergence during treatment. Further analysis indicated coexistence of an activating mutation in EGFR along with a new oncogenic alteration in isolated nuclei, indicating the coexistence of two targetable drivers in all cases. Additionally, significant heterogeneity was exhibited in patient biopsies along with the sequential acquisition of genomic alterations. Using cell lines derived from these patients, it was demonstrated that targeting the observed secondary alterations led to restoration of sensitivity of these cells to osimertinib, which was further confirmed in in vivo models. This study, thus, provides an understanding of the mechanisms behind osimertinib resistance and suggests the benefit of simultaneously targeting bypass mechanisms to restore tumor sensitivity.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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