The evolving landscape of PCSK9 inhibition in cancer

Abstract

Cancer is a disease with a significant global burden in terms of premature mortality, loss of productivity, healthcare expenditures, and impact on mental health. Recent decades have seen numerous advances in cancer research and treatment options. Recently, a new role of cholesterol-lowering PCSK9 inhibitor therapy has come to light in the context of cancer. PCSK9 is an enzyme that induces the degradation of low-density lipoprotein receptors (LDLRs), which are responsible for clearing cholesterol from the serum. Thus, PCSK9 inhibition is currently used to treat hypercholesterolemia, as it can upregulate LDLRs and enable cholesterol reduction through these receptors. The cholesterol-lowering effects of PCSK9 inhibitors have been suggested as a potential mechanism to combat cancer, as cancer cells have been found to increasingly rely on cholesterol for their growth needs. Additionally, PCSK9 inhibition has demonstrated the potential to induce cancer cell apoptosis through several pathways, increase the efficacy of a class of existing anticancer therapies, and boost the host immune response to cancer. A role in managing cancer- or cancer treatment-related development of dyslipidemia and life-threatening sepsis has also been suggested. This review examines the current evidence regarding the effects of PCSK9 inhibition in the context of different cancers and cancer-associated complications.

Keywords: Cancer; Cholesterol; Hypercholesterolemia; Immune response; LDL; PCSK9.

Figure 1.

PCSK9 & LDLR pathway. Both LDLR and PCSK9 are intracellularly synthesized, the former being transported to the plasma membrane and the latter secreted into the plasma. In the absence of PCSK9 binding to LDLR (green arrows), the LDL-LDLR complex is endocytosed, followed by LDL degradation to cholesterol, which is distributed within the cell; simultaneously, LDLR is recycled back to the plasma membrane, where it can continue this cycle. The binding of PCSK9 to LDLR results in LDLR degradation through one of two pathways - an intracellular pathway (red arrows), in which newly synthesized PCSK9 binds to intracellular LDLR and targets its to the lysosome for degradation, and an extracellular pathway (orange arrows), in which secreted PCSK9 binds to the LDLRs on the plasma membrane, resulting in its endocytosis and eventual lysosomal degradation.

Figure 2.

PCSK9 inhibition benefits in cancer and cancer-related outcomes. PCSK9 inhibition has several effects that may be beneficial in the context of cancer. PCSK9 inhibition thwarts PCSK9-mediated degradation of LDLRs, allowing for increased cholesterol clearance and reduced serum cholesterol, which may have anticancer effects by starving cancer cells of cholesterol. PCSK9 inhibition has also been found to induce cancer cell apoptosis and increase the clearance of bacterial LPS and LTA through an LDLR-dependent mechanism, which may be beneficial in the setting of sepsis, to which cancer patients are particularly vulnerable. Lastly, inhibition of PCSK9 boosts the T cell response through a number of mechanisms; these include inhibiting the MHC I downregulation that cancer cells often induce to escape immune detection, demonstrating synergy with and increasing the efficacy of anti-PD1 ICI therapy, and allowing for increased LDLR-mediated TCR recycling. This ability to boost the T cell response may reinstate the host defense against cancer and be useful in protecting against sepsis in already immunosuppressed cancer patients.