Recurrent Escape from Osimertinib-Induced Senescence Promotes Genomic Instability Associated with Therapeutic...

Area of Science:

• Oncology
• Genetics
• Cancer Biology

Background:

• Acquired resistance to osimertinib is a significant clinical problem in EGFR-mutant Non-Small-Cell Lung Cancer (NSCLC).
• Tumor dormancy and eventual relapse are common despite initial treatment response.

Purpose of the Study:

• To investigate the role of osimertinib-induced senescence and subsequent escape in the development of acquired resistance.
• To characterize the genomic alterations associated with resistance emerging from recurrent senescence cycles.

Main Methods:

• Generation of isogenic cell lines through sequential cycles of Osimertinib-Induced Senescence (OsIS).
• Phylogenetic reconstruction using de novo somatic variants to analyze evolutionary trajectories.
• Whole-genome sequencing to identify single-nucleotide variants, copy-number alterations, and mutational signatures.

Main Results:

• Osimertinib induces but does not kill senescent EGFR+ NSCLC cells; drug withdrawal allows escape and proliferation.
• Sequential senescence escape generated distinct resistant cell lines with elevated tumor mutational burden and chromosomal instability.
• Resistance was characterized by extensive loss of heterozygosity, high copy-number alteration burden, and replication-associated DNA damage signatures, not tertiary EGFR mutations or MET amplification.
• A distinct resistance genotype showed extreme focal amplifications and genome remodeling.

Conclusions:

• Recurrent senescence escape is a key driver of osimertinib resistance in EGFR+ NSCLC, mediated by widespread genomic instability.
• Targeting DNA repair or replication stress pathways was ineffective against these resistant cells.
• Platinum-based chemotherapy retained sensitivity, indicating cytotoxic strategies are a promising alternative to targeted therapies for overcoming this resistance mechanism.