Repositioning Aspirin to Treat Lung and Breast Cancers and Overcome Acquired Resistance to Targeted Therapy.

Ling Li,Lu Xu,Hongzhuan Chen,Tao Wang,Mengdi Hu

doi:10.3389/fonc.2019.01503

Abstract

Background: The major limitation of targeted cancer therapy is development of acquired resistance. Intratumoral heterogeneity and coexist of multiple resistance mechanisms make combination therapies targeting one specific mechanism inefficient.Methods: Transcriptional signature obtained from GEO was used to reposition FDA-approved drugs to treat lung and breast cancers as well as overcome acquired resistance to EGFR TKIs in lung cancer and to tamoxifen in breast cancer via CMap. In vitro and in vivo models were used to examine candidate drugs for their anti-cancer and anti-resistance efficacy and underlying mechanisms.Results: We found that aspirin, the most commonly used drug, not only inhibited proliferation and promoted apoptosis of cancer cells, but also delayed and overcame acquired resistance to targeted therapy using in vitro and in vivo models. The underlying mechanism could be attributed to enhanced cancer stemness and activated NF-κB signaling in acquired resistant tumors, both of which were suppressed by aspirin and rendered resistant tumors more sensitive to aspirin.Conclusions: Our data identify aspirin as a potential candidate for combination therapy for lung and breast cancers.

Highlights

The major limitation of targeted cancer therapy is development of acquired resistance
We determined to test the effects of aspirin on the acquired resistance to targeted therapy in lung and breast cancers
We found that aspirin promoted apoptosis by increasing the percentages of apoptotic cells (Figure 2A and Figure S2C) and the expression of cleaved poly ADP-ribose polymerase (PARP) and caspase-3 (Figure 2B)

Summary

Introduction

The major limitation of targeted cancer therapy is development of acquired resistance. Intratumoral heterogeneity and coexist of multiple resistance mechanisms make combination therapies targeting one specific mechanism inefficient. The one major mechanism of acquired resistance to targeted therapy is the alterations in the target itself (on-target), Aspirin Overcome Acquired Resistance such as second mutation T790M in EGFR in EGFR-mutant lung cancer or loss of ER function/expression in ER+ breast cancer. Intratumoral heterogeneity which has been linked to treatment resistance and tumor recurrence as well as coexist of multiple resistance mechanisms render combination therapy targeting one specific molecule or pathway inefficient [5, 6]

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