Harnessing Druggable Synthetic Lethal Interactions in Triple-Negative Breast Cancer with Elevated MYC Expression

The greatest clinical challenge in treating breast cancer occurs in those patients whose tumors lack expression of the estrogen and progesterone receptors and the HER2 oncoprotein. No targeted therapies are currently available for clinical use against this triple-negative breast cancer (TNBC) subtype due to lack of validated molecular targets. TNBC accounts for ~20% of all breast cancer cases and affects young African- American and Hispanic women disproportionately, and also a substantial number of Caucasian women. The molecular and cellular events that may be responsible for driving TNBC have been highly elusive; therefore, the only treatment options currently available are a combination of surgery, radiation, and nonspecific/ conventional cytotoxic chemotherapy. This is in strict contrast to cases of tumors positive for the expression of hormone and HER2 receptors, for which less toxic, targeted therapies have been successfully developed for clinical use (e.g., Herceptin for HER2+ tumors). Patients with TNBC that have received the current standard of care often experience early tumor recurrence and a significantly worse mortality rate. Thus, it is critical to identify and validate clinically viable, life-saving targeted therapies for patients with TNBC, which is the central goal of our research. The lack of such targeted therapies against TNBC is because we know very little about how TNBC occurs and progresses to become lethal. We previously took computational approaches to analyze a large number of patient tumor samples and discovered that a highly potent, cancer-causing protein called MYC was significantly activated in ~50% of all TNBC cases. Our findings were subsequently validated by The Cancer Genome Atlas (TCGA), the national effort to molecularly characterize the biology of breast cancer. Additionally, we found that elevated MYC activity was associated with poor clinical outcomes, suggesting that MYC uniquely contributes to the aggressiveness of TNBC. Due to structural constraints, MYC cannot be directly inhibited by small molecule inhibitors. However, MYC-driven tumors are still able to be challenged. An alternate approach to directly inhibiting undruggable targets such as MYC is to find “synthetic lethal” combinations that selectively kill MYC-driven tumors without affecting healthy cells. The term “synthetic lethality” refers to a genetic context in which a mutation in a gene, which itself is not lethal,can cause lethality when combined with a mutation in another gene. Thus, in the case of MYC, we would like to establish a druggable target that is indispensable only in MYC-driven TNBC cells, but not in healthy cells. We have identified a promising target called PIM and have found that PIM co-exists with MYC in human TNBC samples and that MYC-driven tumors are dependent on PIM to grow in animals continuously. What is promising about PIM is that it is not an essential gene, meaning that the level of potential cytotoxicity is expected to be very low. In fact, several pharmaceutical companies have already generated small molecule PIM inhibitors which are currently being clinically evaluated against liquid tumor types such as leukemia. Thus, the goal of our study is to expand upon our initial findings and establish PIM inhibition as a novel and safe molecularly targeted therapy against TNBC that exhibits abnormally elevated MYC expression (~50% of all TNBC cases). There are numerous potential therapeutic ideas identified in research labs. However, only a fraction of them withstand the phases of human clinical trials. One reas