Overcoming Acquired Drug Resistance to Cancer Therapies through Targeted STAT3 Inhibition

Abstract

Anti-neoplastic agents for cancer treatment utilize many different mechanisms of action and, when combined, can result in potent inhibition of cancer growth. Combination therapies can result in long-term, durable remission or even cure; however, too many times, these anti-neoplastic agents lose their efficacy due to the development of acquired drug resistance (ADR). In this review, we evaluate the scientific and medical literature that elucidate STAT3-mediated mechanisms of resistance to cancer therapeutics. Herein, we have found that at least 24 different anti-neoplastic agents-standard toxic chemotherapeutic agents, targeted kinase inhibitors, anti-hormonal agents, and monoclonal antibodies-that utilize the STAT3 signaling pathway as one mechanism of developing therapeutic resistance. Targeting STAT3, in combination with existing anti-neoplastic agents, may prove to be a successful therapeutic strategy to either prevent or even overcome ADR to standard and novel cancer therapies.

Keywords: STAT3; acquired drug resistance; chemotherapy; immune checkpoint inhibition; kinase inhibitors; monoclonal antibodies.

Figure 1

Graphical schematic depicting molecular mechanism of STAT3-mediated acquired drug resistance in response to receptor tyrosine kinases within cancer cells. Adapted from Yang et al. [144].