Early Adaptive Resistance to Afatinib in PC9 Cells

Abstract

Targeted therapies are commonly used to treat cancer. These therapeutics are made to target and break specific parts of the molecular machinery that causes cancer cells to grow uncontrollably. The smoking-related non-small-cell lung cancer (NSCLC) relies, in 60% of cases, heavily on Epidermal Growth Factor (EGF). EGF signals for cells to grow and this cancer type produces many more EGF receptors (EGFR) than it should, receiving many more growth signals than it should. Drugs that block EGFR signaling, like gefitinib and erlotinib proved to be an effective targeted therapy. However, prolonged treatment resulted in drug-resistant cancer cells, due to mutations in EGFR. New drugs were developed against this EGFR mutant, like afatinib, but once again the cancer would come back having acquired a resistance to the first and second line of drugs. It was discovered that upon the initial treatment with these cancer drugs, a fraction of the cells would survive and that from these cells a resistant cancer would grow. Even if the mutations that cause drug resistance are not present in any cancer cells at the time of treatment, a portion would still survive. In this study, we took a look at the proteins that make up the molecular machinery of NSCLC cells. We observed how adaptations in the regulation of this machinery allowed these cancer cells to survive. We discovered that only cells which are closest to each other survive afatinib treatment and that they make stronger connections between each other. Through these connections, they signal to each other to survive and after three days, to grow again. Inhibiting these survival signals at the same time as afatinib treatment may be enough to prevent cancer recurrence.