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Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

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Mukherjee, D; Previs, RA; Haines, C; Al Abo, M; Juras, PK; Strickland, KC; Chakraborty, B; Artham, S; Whitaker, RS; Hebert, K; Fontenot, J ...
September 1, 2023

<div>Abstract<p>Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2<b>–</b>PDE1A<b>–</b>PKG1<b>–</b>VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.</p>Significance:<p>CaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.</p></div>

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Publication Date

September 1, 2023
 

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Mukherjee, D., Previs, R. A., Haines, C., Al Abo, M., Juras, P. K., Strickland, K. C., … McDonnell, D. P. (2023). Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. https://doi.org/10.1158/0008-5472.c.6816225
Mukherjee, Debarati, Rebecca A. Previs, Corinne Haines, Muthana Al Abo, Patrick K. Juras, Kyle C. Strickland, Binita Chakraborty, et al. “Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis,” September 1, 2023. https://doi.org/10.1158/0008-5472.c.6816225.
Mukherjee D, Previs RA, Haines C, Al Abo M, Juras PK, Strickland KC, et al. Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. 2023.
Mukherjee, Debarati, et al. Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. 1 Sept. 2023. Crossref, doi:10.1158/0008-5472.c.6816225.
Mukherjee D, Previs RA, Haines C, Al Abo M, Juras PK, Strickland KC, Chakraborty B, Artham S, Whitaker RS, Hebert K, Fontenot J, Patierno SR, Freedman JA, Lau FH, Burow ME, Chang C-Y, McDonnell DP. Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. 2023.

DOI

Publication Date

September 1, 2023