Synergistic Molecular Strategies for Targeting the Unfolded Protein Response in Cancer Therapy

Targeted synergistic therapies represent a rapidly developing branch of oncology. The emergence of novel targeting agents allows for modulation of an ever-larger set of cellular pathways. The Unfolded Protein Response (UPR) is a key element of cellular proteostasis that is significantly hyperactivated in a wide range of cancer cell types, especially those with high secretory activity. As cancer cells are especially vulnerable to endoplasmic reticulum stress (ER Stress), they become heavily dependent on UPR function to maintain homeostasis. A wide number of pharmacologic agents can stimulate the UPR and shift it from its initial pro-survival phase to the terminal pro-apoptotic phase. Key strategies include the use of UPR feedback inhibitors (e.g., GRP78 antagonists), direct pathway inhibitors targeting the PERK or IRE1α branches, and signal pathway modulators (e.g., TKIs and BTK inhibitors) that indirectly exacerbate proteotoxic stress. In this study we provide a mechanistic framework where we classify synergistic therapies based on their mechanism of action and explore how they influence ER Stress and UPR activation. Evidence synthesized from these studies suggests that synergistic combinations can overcome therapeutic resistance and selectively induce apoptosis in cancer cells characterized by high proteotoxic stress.