PROJECT SUMMARY/ABSTRACT
Triple-negative breast cancer (TNBC) refers to a collection of heterogeneous breast tumors that lack expression
of immediately druggable molecules, such as the estrogen and progesterone receptors and human epidermal
growth factor receptor 2. No targeted therapy is currently approved for the vast majority of TNBC patients. TNBC
patients who have received the current standard of care, consisting of chemotherapy, radiation, and surgery,
often experience early tumor recurrence and a significantly worse mortality rate. Therefore, it is critical to identify
and validate clinically viable, life-saving targeted therapies for patients with TNBC. We previously reported that
the oncogenic MYC pathways were activated in ~50% of TNBC cases compared with non-TNBC cases and that
MYC levels were associated with poor outcomes among TNBC patients. Unfortunately, clinical development of
inhibitors that directly target MYC activity has remained challenging. To overcome this challenge, we previously
took an alternative approach known as the synthetic lethal screening approach to identify readily druggable
targets required for MYC-driven tumor viability but that are not essential in non-tumor cells. Our screen identified
the PIM family of kinases, which is composed of the closely related nonessential kinase isoforms PIM1, -2, and
-3 (PIM hereafter), as a promising target in MYC-driven TNBC. We found that PIM expression was elevated in
triple-negative (TN) tumors in clinical samples and was associated with poor patient outcomes. Clinically relevant
pan-PIM inhibitors showed activity in various experimental models of TNBC. However, our single-agent efficacy
studies using preclinical PIM inhibitors showed that although PIM inhibition significantly slowed the growth of TN
tumors, it induced only modest in vivo tumor cell death and regression, suggesting the need for combination
therapies. We have taken robust drug screening approaches and have unexpectedly found that the drug
combination that targets PIM kinases and the proteasome can acutely induce toxic levels of proteotoxic stress
selectively in MYC-overexpressing TNBC cells. Mechanistically, our preliminary observations indicate that PIM
inhibition, which elevates the levels of reactive oxygen species, when combined with proteasome inhibition,
overwhelms the capacity of TNBC cells to continuously degrade damaged proteins, resulting in proteotoxic crisis.
Thus, our observations raise the possibility—and our study will test the hypothesis—that PIM inhibition
represents a unique and clinically viable tool to sensitize TNBC tumors to proteasome inhibition. The successful
execution of this research will allow for the identification and interrogation of clinically exploitable vulnerabilities
in MYC-driven solid-cancer types such as TNBC. The outcomes of this research could also encourage the FDA-
approved proteasome inhibitors (e.g., carfilzomib), which have not been successfully used outside of liquid tumor
types, to be rapidly evaluated in combination with pan-PIM kinase inhibitors in early-stage MYC-driven solid-
tumor trials.