Resistance to HER2-Targeted Therapies Results in Upregulation of MCL-1 and Sensitivity to Olaparib

HER2 amplification results in increased tumor growth and aggressiveness in breast cancer. Despite advancements in HER2-targeted therapy, treatment resistance, cancer recurrence, and metastasis remain significant obstacles in combating this deadly disease. PARP inhibitors, have emerged as a promising class of drugs targeting cancers deficient in homologous recombination repair. Recent preclinical evidence suggests that PARP inhibitors exhibit sensitivity in cancers with high replication stress and genomic instability, as well as some HER2 positive breast cancer cell lines. To investigate the relationship between HER2 amplification and PARP inhibitor sensitivity, we utilized isogenic models of HER2-positive breast cancer, whereby cells were either sensitive or resistant to lapatinib and treated with the PARP inhibitor olaparib used as a single agent, or in combination with HER2-targeted therapies. Our results show that HER2 overexpressing MCF-10A cells are highly sensitivity to single-agent olaparib. The addition of trastuzumab and lapatinib resulted in a synergistic increase in toxicity. To determine if olaparib could be used to overcome resistance to lapatinib, we obtained SKBR3 cells conditioned to be resistant to lapatinib. Despite resistance to lapatinib, these cells continue to exhibit sensitivity to olaparib. Reverse phase protein analysis revealed that lapatinib resistant clones exhibited a statistically-significant increase in protein expression of the apoptosis inhibitor MCL-1, which is decreased upon olaparib treatment resulting in apoptosis. Taken together, our findings suggest that HER2 overexpression may predict sensitivity to olaparib alone, or in combination with trastuzumab and lapatinib. Lapatinib resistant HER2-positive breast cancer cells are sensitive to olaparib, possibly through downregulation of MCL-1.