Oncotarget

Research Papers:

GZ17-6.02 kills PDX isolates of uveal melanoma

Laurence Booth, Jane L. Roberts, Ivan Spasojevic, Kaitlyn C. Baker, Andrew Poklepovic, Cameron West, John M. Kirkwood and Paul Dent _

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Oncotarget. 2024; 15:328-344. https://doi.org/10.18632/oncotarget.28586

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Abstract

Laurence Booth1, Jane L. Roberts1, Ivan Spasojevic3, Kaitlyn C. Baker1, Andrew Poklepovic2, Cameron West4,5, John M. Kirkwood6 and Paul Dent1

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

2 Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA

3 Department of Medicine, and PK/PD Core Laboratory, Duke University School of Medicine, Durham, NC 27710, USA

4 Genzada Pharmaceuticals, Hutchinson, KS 67502, USA

5 Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA

6 Melanoma and Skin Cancer Program, Hillman Cancer Research Pavilion Laboratory, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA

Correspondence to:

Paul Dent, email: [email protected]

Keywords: autophagy; ER stress; GZ17-6.02; doxorubicin; afatinib; neratinib

Received: April 04, 2024     Accepted: May 06, 2024     Published: May 17, 2024

Copyright: © 2024 Booth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.


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