An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Lung cancer is a leading cause of cancer mortality globally.
• Drug resistance, particularly to EGFR tyrosine kinase inhibitors (TKIs), is a major challenge in treating non-small cell lung cancer (NSCLC).
• AXL and GAS6 overexpression contribute to resistance against TKIs like Erlotinib and Osimertinib in certain NSCLC subtypes.

Purpose of the Study:

• To investigate the ontogeny of AXL-positive cells and identify novel mechanisms of drug resistance in EGFR-mutated NSCLC.
• To understand the role of cell-state transition in the emergence of drug-resistant cancer cell subpopulations.
• To explore the epigenetic regulation of AXL expression and its link to drug resistance.

Main Methods:

• Analysis of AXL-positive cell subpopulations in Erlotinib-naïve tumors and cell lines.
• Investigation of the epigenetic regulation of miR-335 in controlling AXL expression.
• Studying cell-state transition as a non-genetic mechanism of drug resistance.

Main Results:

• AXL-positive cells, conferring Erlotinib resistance, exist as a pre-existing subpopulation in EGFR-mutated NSCLC.
• AXL expression is regulated by a stochastic, epigenetic mechanism involving miR-335.
• This identifies a cell-intrinsic program driving the emergence of resistant cells.

Conclusions:

• A novel non-genetic mechanism of drug resistance via cell-state transition has been identified in EGFR-mutated NSCLC.
• The findings highlight the importance of targeting both AXL-negative and AXL-positive cancer cells simultaneously.
• Upfront combinatorial treatment strategies are necessary to overcome drug resistance in these tumors.