GZ17-6.02 Interacts With [MEK1/2 and B-RAF Inhibitors] to Kill Melanoma Cells

Abstract

We defined the lethal interaction between the novel therapeutic GZ17-6.02 and the standard of care combination of the MEK1/2 inhibitor trametinib and the B-RAF inhibitor dabrafenib in PDX isolates of cutaneous melanoma expressing a mutant B-RAF V600E protein. GZ17-6.02 interacted with trametinib/dabrafenib in an additive fashion to kill melanoma cells. Regardless of prior vemurafenib resistance, the drugs when combined interacted to prolong ATM S1981/AMPK T172 and eIF2α S51 phosphorylation and prolong the reduced phosphorylation of JAK2 Y1007, STAT3 Y705 and STAT5 Y694. In vemurafenib-resistant cells GZ17-6.02 caused a prolonged reduction in mTORC1 S2448, mTORC2 S2481 and ULK1 S757 phosphorylation; regardless of vemurafenib resistance, GZ17-6.02 caused a prolonged elevation in CD95 and FAS-L expression. Knock down of eIF2α, Beclin1, ATG5, ATM, AMPKα, CD95 or FADD significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with the kinase inhibitors. Expression of activated mTOR, activated STAT3, activated MEK1 or activated AKT significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with kinase inhibitors; protective effects that were significantly less pronounced in cells treated with trametinib/dabrafenib. Regardless of vemurafenib resistance, the drugs alone or in combination all reduced the expression of PD-L1 and increased the levels of MHCA, which was linked to degradation of multiple HDAC proteins. Our findings support the use of GZ17-6.02 in combination with trametinib/dabrafenib in the treatment of melanomas expressing mutant B-RAF V600E proteins.

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

“…Palbociclib and 5FU were purchased from Selleckchem (Houston, TX). All Materials were obtained as described in the references [1][2][3][4][5]. Trypsin-EDTA, DMEM, RPMI, penicillin-streptomycin were purchased from GIBCOBRL (GIBCOBRL Life Technologies, Grand Island, NY).…”

“…Trypsin-EDTA, DMEM, RPMI, penicillin-streptomycin were purchased from GIBCOBRL (GIBCOBRL Life Technologies, Grand Island, NY). Other reagents and performance of experimental procedures were as described [1][2][3][4][5]. Antibodies were purchased from Cell Signaling Technology (Danvers, MA); Abgent (San Diego, CA); Novus Biologicals (Centennial, CO); Abcam (Cambridge, UK); and Santa Cruz Biotechnology (Dallas, TX).…”

“…The therapeutic agent GZ17-6.02 has three components: curcumin, harmine and isovanillin [1][2][3][4][5]. It is currently undergoing phase I safety evaluation in cancer patients with solid tumors and lymphoma (NCT03775525).…”

“…It is currently undergoing phase I safety evaluation in cancer patients with solid tumors and lymphoma (NCT03775525). Our prior studies have shown that GZ17-6.02 kills a range of tumor cell types, including colorectal, pancreatic, hepatic, biliary, NSCLC, melanoma, sarcoma and actinic keratoses [1][2][3][4][5]. GZ17-6.02 interacted with 5FU in vivo to suppress the growth of colorectal tumor cells and in vivo to prolong animal survival [6].…”

“…GZ17-6.02 interacted with 5FU in vivo to suppress the growth of colorectal tumor cells and in vivo to prolong animal survival [6]. The mechanisms by which GZ17-6.02 interacted with drugs such as 5FU, pemetrexed and dabrafenib/trametinib to kill tumor cells were similar: toxic autophagic flux, activation of death receptor signaling and mitochondrial dysfunction [1][2][3][4][5][6]. However, the biology of GZ17-6.02 in estrogen receptor (ER) positive breast cancer is presently unknown.…”