Medicine and Health Sciences Commons^™

Mapk Reliance Via Acquired Cdk4/6 Inhibitor Resistance In Cancer., Renée De Leeuw, Christopher Mcnair, Matthew J. Schiewer, Neermala Poudel Neupane, Lucas J. Brand, Michael A. Augello, Zhen Li, Larry C. Cheng, Akihiro Yoshida, Sean M. Courtney, E. Starr Hazard, Gary Hardiman, Maha H. Hussain, J. Alan Diehl, Justin M. Drake, William Kevin Kelly, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

Purpose: Loss of cell-cycle control is a hallmark of cancer, which can be targeted with agents, including cyclin-dependent kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G₁-S cell-cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon.

Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer.

Results: This study demonstrates that acquired palbociclib resistance renders cancer …

Concurrent Regulation Of Lkb1 And Camkk2 In The Activation Of Ampk In Castrate-Resistant Prostate Cancer By A Well-Defined Polyherbal Mixture With Anticancer Properties., Amber F. Macdonald, Ahmed Bettaieb, Dallas R. Donohoe, Dina S. Alani, Anna Han, Yi Zhao, Jay Whelan

Department of Cancer Biology Faculty Papers

BACKGROUND: Zyflamend, a blend of herbal extracts, effectively inhibits tumor growth using preclinical models of castrate-resistant prostate cancer mediated in part by 5'-adenosine monophosphate-activated protein kinase (AMPK), a master energy sensor of the cell. Clinically, treatment with Zyflamend and/or metformin (activators of AMPK) had benefits in castrate-resistant prostate cancer patients who no longer responded to treatment. Two predominant upstream kinases are known to activate AMPK: liver kinase B1 (LKB1), a tumor suppressor, and calcium-calmodulin kinase kinase-2 (CaMKK2), a tumor promotor over-expressed in many cancers. The objective was to interrogate how Zyflamend activates AMPK by determining the roles of LKB1 and …

Differential Impact Of Rb Status On E2f1 Reprogramming In Human Cancer., Christopher Mcnair, Kexin Xu, Amy C. Mandigo, Matteo Benelli, Benjamin E. Leiby, Daniel Rodrigues, Johan Lindberg, Henrik Gronberg, Mateus Crespo, Bram De Laere, Luc Dirix, Tapio Visakorpi, Fugen Li, Felix Y. Feng, Johann De Bono, Francesca Demichelis, Mark A. Rubin, Myles Brown, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

The tumor suppressor protein retinoblastoma (RB) is mechanistically linked to suppression of transcription factor E2F1-mediated cell cycle regulation. For multiple tumor types, loss of RB function is associated with poor clinical outcome. RB action is abrogated either by direct depletion or through inactivation of RB function; however, the basis for this selectivity is unknown. Here, analysis of tumor samples and cell-free DNA from patients with advanced prostate cancer showed that direct RB loss was the preferred pathway of disruption in human disease. While RB loss was associated with lethal disease, RB-deficient tumors had no proliferative advantage and exhibited downstream effects …