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The retinoblastoma tumor suppressor (RB) is an important regulator of the cell cycle and a multitude of other processes that are germane to tumor development. The functional inactivation of RB has been recognized to occur sporadically in a large fraction of human tumors where it is believed to contribute to disease initiation and/or progression. Several studies have now shown that the specific loss of this tumor suppressor represents a selective vulnerability that could be targeted therapeutically and therefore provide a precision approach to exploiting RB loss [1-5]. RB-pathway and breast cancer: Breast cancer is a heterogeneous disease, wherein different manifestations impact prognosis and standard of care regimens. Typically, the presence of estrogen receptor (ER) and progesterone receptor (PR) or epidermal growth factor receptor 2 (HER2) amplification status delineates a course of treatment. Tumors that are HER2 positive are treated with drugs that target this oncogene (e.g. trastuzumab or lapatininb), while ER/PR positive tumors can be treated based on dependence on estrogen (e.g. tamoxifen or letrozole). Tumors that lack ER/PR and HER2 are termed triple-negative breast cancer (TNBC) and are treated systemically with chemotherapy due to the absence of a defined target for therapeutic intervention. RB is believed to be inactivated as a result of two different mechanisms in breast cancer [6]. 1. RB gene loss, typically as a result of homozygous deletion, occurs predominantly in triple negative breast cancer. This event is relatively rare in ER/PR or Her2 positive cancers at diagnosis. However, in the metastatic setting following treatment with endocrine therapy there is selection for increased loss of RB [7]. 2. RB can also be inactivated by phosphorylation that is initiated by CDK4/6 containing complexes. In breast cancers, amplification of the positive regulators Cyclin D1 and CDK4/6, or loss of the negative regulator p16ink4a are all known to occur [8]. Additionally, a plethora of other events can lead to aberrant CDK4/6 activity that deregulates the normal controls over RB phosphorylation. The importance of CDK4/6 as a therapeutic target is now well-established in ER/PR positive breast cancer where palbociclib, ribociclib and abemaciclibe are all FDA approved. Even though these agents are effective, it is clear that disease progression can occur and this is associated with the selection for RB loss [9]. Thus, defining means to selectively target RB loss could represent a new targeted approach for TNBC, and could represent an important avenue for the treatment of ER/PR positive tumors that progress on CDK4/6 inhibitor treatment. Selective targeting of RB loss: Two recent studies have provided new insights into how the loss of RB could be exploited as a unique vulnerability in breast cancer [2, 5]. Both studies used a combination of drug screens and functional studies coupled with the analysis of clinical populations to credential drug targets and delineate mechanisms of therapeutic sensitivity. The study from Witkiewicz et al. began with the premise of defining drugs that were specifically modified by the activation status of RB. RB can be activated with CDK4/6 inhibitors and therefore screens were performed in RB-proficient models identifying drugs where cytotoxicity was antagonized by CDK4/6 inhibition. Parallel screens were carried out with panels of TNBC cell lines that had either intrinsically different RB-status, or matched models where RB had been selectively abrogated with CRISPR or ShRNA approaches. From a large number of drugs, essentially three classes of targeted drugs emerged from this investigation: 1. CHK1 inhibitors; 2. PLK1 inhibitors; and 3. Aurora Kinase inhibitors. Importantly, each of these kinases is expressed at higher levels in RB-deficient tumors. Mechanistic analysis suggested that RB loss contributes to sensitivity to CHK1 Editorial

The vulnerability of RB loss in breast cancer: Targeting a void in cell cycle control