Tumor Suppressor PLK2 May Serve as a Biomarker in Triple-Negative Breast Cancer for Improved Response to PLK1 Therapeutics

Abstract

Polo-like kinase (PLK) family members play important roles in cell-cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, frequent loss of chromosome 5q11–35, which includes PLK2, is observed in basal-like breast cancer. In this study, we found that PLK2 was tumor suppressive in breast cancer, preferentially in basal-like and triple-negative breast cancer (TNBC) subtypes. Knockdown of PLK1 rescued phenotypes induced by PLK2 loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase through the kinase but not the polo-box domains of PLK2, suggesting PLK2 functioned at least partially through the interaction with PLK1. Furthermore, an improved treatment response was seen in both Plk2-deleted/low mouse preclinical and patient-derived xenograft (PDX) TNBC models using the PLK1 inhibitor volasertib alone or in combination with carboplatin. Reexpression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. In summary, this study delineates the effects of chromosome 5q loss in TNBC that includes PLK2, the relationship between PLK2 and PLK1, and how this may render PLK2-deleted/low tumors more sensitive to PLK1 inhibition in combination with chemotherapy. Significance: The tumor-suppressive role of PLK2, and its relationship with oncogene PLK1, provide a mechanistic rationalization to use PLK1 inhibitors in combination with chemotherapy to treat PLK2-low/deleted tumors. TNBC, and other cancers with low PLK2 expression, are such candidates to leverage precision medicine to identify patients who might benefit from treatment with these inhibitors.

Unraveling Biomarker Signatures in Triple-Negative Breast Cancer: A Systematic Review for Targeted Approaches

“…Shedding light on PLK2′s role, experiments involving shRNA-induced knockdown resulted in a notable increase in colony numbers compared to controls. This suggests a tumor-suppressive role for PLK2, found to be mediated by a direct interaction of PLK2 with PLK1, whose overexpression is involved in TNBC growth [ 19 ]. Furthermore, in TNBC models with PLK2 deletion/low expression, treatment with PLK1 inhibitor volasertib, alone or combined with carboplatin, led to an improved treatment response, providing a rationale for using this approach to treat tumors with low or deleted PLK2 [ 19 ].…”

Landscape of Genetic Alterations Underlying Hallmark Signature Changes in Cancer RevealsTP53Aneuploidy–driven Metabolic Reprogramming

“…In MDS, 5q deletion causes haploinsufficiency of several genes ( 52 ), including RPS14 , CSNK1A1 , APC , DDX41 , and miR-145/miR-146a, leading to deregulated p53-mediated apoptosis, WNT/β-catenin, and inflammatory signaling. In addition to these genes, many 5q genes are involved in diverse hallmark signature changes driving oncogenesis: RAD17 and RAD50 are directly involved in DNA double-strand break repair ( 53 ); MAP3K1 is a repressor of the mitogen-activated protein (MAP)-kinase pathway and regulates several survival and/or proliferation pathways ( 54 ); and PLK2 is involved in MTORC1 signaling ( 55 ) and as a biomarker for treatment in triple-negative breast cancer ( 56 ). Further experimental work is required to explore the individual consequence of deletion of these genes within the 5q region in the basal-like/squamous tumors.…”

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

“…Modulation of their activity may impair crucial cellular functions, like cell division. It is also possible that some compensatory effects would compromise the therapeutic benefit [ 356 , 357 ]. It needs to be assessed which isoforms would be the most therapeutic, and also which approach is more beneficial to target, activation or inhibition.…”