Induced myeloid leukemia cell differentiation protein (MCL1) is a crucial member of the B-cell lymphoma-2 (BCL2) family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. PRT1419 is a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies.

To validate the therapeutic feasibility of MCL1 inhibition in clear cell Renal Cell Carcinoma (ccRCC), researchers sought to investigate PRT1419 in a cell-line derived xenograft (CDX) model of PBRM1-mutant ccRCC. OS-RC-2 harbors a missense mutation in the PBRM1 bromodomain as a potential system to model PBRM1 loss in vivo. Importantly, OS-RC-2 lacks PBRM1 protein expression and can be transplanted into nude mice, generating tumors with histopathological features which closely resemble clinical ccRCC.

For the OS-RC-2 model, 1x10⁶ OS-RC-2 cells were injected into the right flank of 6–9-week-old female BALB/c nude mice.

When the tumors were ~200 mm³, mice were randomized into two groups. Animals were either treated with vehicle or 20 mg/kg of PRT1419 administered intravenously, once weekly for three weeks. Researchers observed 42% Tumor Growth Inhibition (TGI) in response to PRT1419 treatment. PRT1419 dosing was well tolerated with no notable body weight loss or behavioral changes. Altogether these findings suggest PBRM1 loss in ccRCC is associated with MCL1 dependency and sensitivity to MCL1 inhibition.

CDX studies were performed at Medicilon (OS-RC-2). All studies were performed in accordance with animal research guidelines from Medicilon.

Reference:

Norman Fultang, et al. PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer. Front Oncol. 2024 Feb 2:14:1343004. doi: 10.3389/fonc.2024.1343004.