ALDH1A1 Expression Confers Lung Tumor Resistance to Gefitinib and Chemotherapy Agents

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(ChemotherapyAdvisor) – Lung cancer stem cell expression of the ALDH1A1 aldehyde dehydrogenase gene might explain lung tumor resistance to chemotherapy agents and gefitinib, a targeted molecular EGFR tyrosine kinase inhibitor, according to a study published in Cancer Letters.

“We have provided evidence that ALDH1A1-positive lung cancer cells display significant resistance to EGFR-TKI (gefitinib) and anti-cancer chemotherapeutic drugs (cisplatin, etoposide and fluorouracil), compared to ALDH1A1-negative lung cancer cells,” reported lead author Jin-Yuan Shih, MD, PhD, National Taiwan University Hospital, Taipei, Taiwan, and colleagues.

Lung cancer involving EGFR L858R and exon-19 deletion mutations, show initial clinical response to targeted molecular EGFR-TKIs. But in most patients, tumors develop resistance and relapse. Cancer stem cells (CSCs) are believed to be responsible for tumor resistance to conventional chemotherapies, but their potential role in EGFR-TKI resistance in lung cancers had not been studied, the authors noted.

The new study assessed EGFR-TKI and chemotherapy-agent sensitivity in ALDH1A1-positive and negative cell lines derived from PC9 gefitinib-sensitive lung tumors and clinical samples of malignant pleural effusions (MPEs), exposing cells to gefitinib, cisplatin, etoposide, or fluorouracil for 72 hours before determining cell viabilities. ALDH1A1-positive cells were significantly more resistant to these agents than ALDH1A1-negative cells, the authors reported – suggesting a role for ALDH1A1 in gefitinib resistance.

The authors reported that 6.5% of gefitinib-sensitive cells were ALDH1A1-positive, compared to 37.8% of gefitinib-resistant cells – a 6-fold difference.

“Our findings suggest that ALDH1A1-positive cancer stem cells promote both EGFR-TKI and chemotherapy resistance in lung cancer,” they wrote. “Thus, strategies aimed at killing ALDH1A1-positive lung cancer stem cells may present a more reliable approach to overcome EGFR-TKI resistance and develop effect treatments for lung cancer.”

Gefitinib is marketed by AstraZeneca as Iressa.


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