Recent studies have reported the ability of drug-resistant cancer cells to acquire mitogenic signals from previously neglected autocrine loops, causing tumor recurrence.
For example, despite widespread expression of epidermal growth factor receptors (EGFRs) and EGF family ligands in non-small-cell lung cancer (NSCLC), EGFR-specific tyrosine kinase inhibitors such as gefitinib have shown limited therapeutic success. This resistance is proposed to be because autocrine growth signaling pathways distinct from EGFR are active in NSCLC cells. Gene expression profiling revealed the prevalence of specific fibroblast growth factors (FGFs) and FGF receptors in NSCLC cell lines, and found that FGF2, FGF9 and their receptors encompass a growth factor autocrine loop that is active in a subset of gefitinib-resistant NSCLC cell lines.
In breast cancer, the acquisition of tamoxifen resistance is another major therapeutic problem. It has been shown that phosphorylation of STAT3 and RANTES expression are increased in response to tamoxifen in human breast cancer cells. In a recent study, one group showed that STAT3 and RANTES contribute to the maintenance of drug resistance by upregulating anti-apoptotic signals and inhibiting caspase cleavage. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors.