Lung cancer stem cells and their aggressive progeny, controlled by EGFR/MIG6 inverse expression, dictate a novel NSCLC treatment approach


The cover for issue 26 of Oncotarget features Figure 2, "LuCSC-holoclones initiate rim-like niches and their differentiation creates pseudo-alveoli structures," by Xiao, et al.

Metastatic non-small cell lung cancer (NSCLC) cannot be cured with systemic chemotherapy and only 4% have a 5 year survival rate after postoperative chemotherapy. This strongly indicates that the improvement of long term patient survival will require more effective systemic therapies.

The tumor hierarchical model suggests that cancer stem cells, which represent a biologically distinct subset within the total cancer cell population, have the principal properties of self-renewal, clonal tumor initiation capacity and clonal long-term repopulation potential.

Dr. Pjotr G. Knyazev from the Department of Molecular Biology, at the Max-Planck Institute of Biochemistry, in Martinsried, Munich, 82152, Germany and Dr. Zhiguang Xiao from the Department of Molecular Biology, at the Max-Planck Institute of Biochemistry, in Martinsried, Munich, 82152, Germany and the Department of Medicine, at the University of Rochester School of Medicine and Dentistry, in Rochester, NY 14642, USA said "EGFR naivety in epithelial lung cancer stem cells (LuCSCs) contributes to TKI resistance in NSCLC."

Figure 1: NSCLC cell line model (NCI-H1568) exhibits unique cellular heterogeneity and functional characteristic.

The epithelial LuCSCs were lineage naïve, noninvasive and able to initiate rimmed niches. The regulation of LuCSC transition from self-renewal to differentiation could be highly connected to the activation of EGFR signaling and the inverse inhibition of MIG6. Differentiated aggressive progeny (almost no stemness) possess exclusive growth efficiency in serum-depleted culture condition due to high expressions of EGFR and its ligands as well as AXL/GAS6, providing them autologous signal for proliferation and survival.

Importantly, drug screening demonstrated that EGFR driving progeny were strongly responsive to TKIs; however, the LuCSCs were exclusively resistant but sensitive to AMPK agonist Metformin, antibiotic Salinomycin and to a lesser degree Carboplatin.

To expose the clinical relevance of the study, they further compared the IC50s of the tested drugs and their maximum plasma concentrations in patients. They found that the tested concentrations of drugs which differentiate between resistance and sensitivity are in a range that can be achieved in patient plasma.

The Knyazev/Xiao research team concluded, "successful lung cancer treatment requires combinatorial application or a novel approach to target both LuCSCs and differentiated tumor cells.

Full text - https://doi.org/10.18632/oncotarget.26817

Correspondence to - Pjotr G. Knyazev - [email protected] and Zhiguang Xiao - [email protected]

Keywords - NSCLC, cancer stem cells, niches, EGFR/MIG6, drug resistance

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