CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer.

Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models.

CDK4/6 inhibitors promote PARP1 degradation and act synergistically with PARP inhibitors in non-small cell lung cancer.

Despite the widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), the clinical trials with CDK4/6 inhibitors (CDK4/6is) as a monotherapy have shown poor antitumor activity. However, our preclinical studies have revealed a significant potential for CDK4/6is to collaborate by influencing DNA damage repair pathways during radiotherapy. Given the considerable upregulation of PARP1 expression in NSCLC, we analyzed the efficacy of combined PARP and CDK4/6 inhibition in NSCLC models.

Evaluating physiochemical properties of FDA-approved orally administered drugs.

Introduction: Analyses of orally administered FDA-approved drugs from 1990 to 1993 enabled the identification of a set of physiochemical properties known as Lipinski's Rule of Five (Ro5). The original Ro5 and extended versions still remain the reference criteria for drug development programs. Since many bioactive compounds do not conform to the Ro5, we validated the relevance of and adherence to these rulesets in a contemporary cohort of FDA-approved drugs.

Dynamic differences between DNA damage repair responses in primary tumors and cell lines.

The study of DNA damage repair response (DDR) in prostate cancer is restricted by the limited number of prostate cancer cell lines and lack of surrogates for heterogeneity in clinical samples. Here, we sought to leverage our experience with patient derived explants (PDEs) cultured ex vivo to study dynamics of DDR in primary tumors following application of clinically relevant doses of ionizing radiation (IR) to tumor cells in their native 3-dimensional microenvironment. We compared DDR dynamics between prostate cancer cell lines, PDEs and xenograft derived explants (XDEs) following treatment with IR (2Gy) either alone or in combination with pharmacological modulators of DDR.