Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Mechanisms of acquired resistance to EGFR inhibitors in non-small-cell lung cancer (NSCLC) are known, but resistance evolution pathways are unclear.
• The EGFR T790M gatekeeper mutation is a key mechanism of acquired resistance.
• Drug-tolerant cells may represent a precursor to resistant clones.

Purpose of the Study:

• To investigate the evolutionary pathways of acquired resistance in EGFR-mutant NSCLC during EGFR inhibitor therapy.
• To determine if resistant clones pre-exist or evolve from drug-tolerant cells.
• To identify therapeutic strategies to overcome acquired resistance.

Main Methods:

• Utilized cell cultures and patient-derived tumor cultures.
• Analyzed the emergence of EGFR T790M mutations.
• Assessed apoptotic responses to EGFR inhibitors and navitoclax.
• Investigated the role of BCL-xL and BCL-2 in resistance.

Main Results:

• Acquired resistance can occur through selection of pre-existing EGFR T790M-positive clones or evolution from EGFR T790M-negative drug-tolerant cells.
• Resistant clones evolved from drug-tolerant cells showed reduced apoptosis sensitivity to third-generation EGFR inhibitors.
• Treatment with navitoclax restored sensitivity in these resistant cells.
• Findings were validated in patient-derived resistant tumor cultures.

Conclusions:

• Clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant states.
• The evolutionary path to resistance influences cellular biology and drug response.
• Targeting anti-apoptotic factors like BCL-xL/BCL-2 presents a therapeutic opportunity to prevent or overcome EGFR inhibitor resistance.