Abstract
While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer.
Highlights
Breast cancer is the most common malignancy in women, and one of the three most common cancers worldwide [1]
Despite the initial success of anti-cyclin-dependent kinases 4 and 6 (CDK4/6) agents such as palbociclib in estrogen receptor (ER)+ breast cancers, drug resistance remains a major challenge for a significant subset of patients
We found that OAdmCherry infection induced type I IFN response as shown by the increase in signal transducer and activator of transcription 1 (STAT1) phosphorylation compared to uninfected control and adenovirus expressing green fluorescent protein (AdGFP) infected in MCF7/pS cells but not in MCF7/pR cells (Figure 5B)
Summary
Breast cancer is the most common malignancy in women, and one of the three most common cancers worldwide [1]. While endocrine treatment is an effective first-line therapy for ER+ breast cancer, its success is limited by either intrinsic or acquired resistance [5]. (CDK4/6), leading to cell cycle progression, even in the absence of estrogen [6,7,8,9]. These observations prompted the development of the first-in-class, oral, small-molecule inhibitor of the catalytic domains of CDK4/6, palbociclib (PD-0332991, Ibrance) [10,11,12,13,14]. Three orally bioavailable CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) have been FDA-approved for the treatment of advanced ER+ breast cancer [15]. Intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; the development of various strategies to overcome this resistance is of great importance
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