Research Papers:

GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells

Laurence Booth, Cameron West, Robert P. Moore, Daniel Von Hoff and Paul Dent _

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Laurence Booth1, Cameron West2, Robert P. Moore2, Daniel Von Hoff3 and Paul Dent1

1 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA

2 Genzada Pharmaceuticals, Sterling, KS 67579, USA

3 Physician-in-Chief, Distinguished Professor, Translational Genomics Research Institute (TGEN), Phoenix, AZ 85004, USA

Correspondence to:

Paul Dent, email: [email protected]

Keywords: GZ17-6.02; palbociclib; 5FU; autophagy; breast cancer

Received: October 25, 2021     Accepted: December 08, 2021     Published: January 11, 2022

Copyright: © 2022 Booth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


GZ17-6.02 is presently undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in estrogen receptor positive breast cancer cells and to determine whether it interacted with palbociclib to enhance tumor cell killing. GZ17-6.02 interacted in an additive fashion with palbociclib to kill ER+ breast cancer cells. GZ17-6.02 and palbociclib cooperated to inactivate mTOR and AKT and to activate ULK1 and PERK. The drugs interacted to increase the expression of FAS-L and BAX, and to decrease the levels of MCL1, the estrogen receptor, and HDACs 1–3. Palbociclib activated ERBB3, an effect blocked by GZ17-6.02. GZ17-6.02 and palbociclib interacted to increase the expression of multiple toxic BH3 domain proteins and to reduce MCL1 and BCL-XL expression. Knock down of FAS-L reduced the lethality of [GZ17-6.02 + palbociclib]. GZ17-6.02 and palbociclib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, BAG3, eIF2α, toxic BH3 domain proteins or CD95 significantly reduced drug combination lethality. GZ17-6.02 and palbociclib increased the expression of Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs also increased the phosphorylation of the AMPK and ATG13, effects blocked by knock down of ATM. Knock down of ATM or the AMPK, or expression of activated mTOR significantly reduced the abilities of GZ17-6.02 and palbociclib to enhance autophagosome formation and autophagic flux.

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