CDK4/6 Inhibitors Effective in Mice Bearing Multiple Human Cancer Types

BOSTON – Cyclin-dependent kinase (CDK) inhibitors, including palbociclib, were effective against patient-derived xenograft (PDX) mouse models of different tumor types, including hormone receptor (HR)-negative breast cancer, gastric cancer, and colorectal cancer, according to data presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 26-30.

Three CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced HR-positive, HER2-negative breast cancer – palbociclib (Ibrance), abemaciclib (Verzenio), and ribociclib (Kisqali).

“The main goal of our study was to try to identify other tumor types that might benefit from CDK inhibition,” said Michael J. Wick, PhD, director of preclinical research at South Texas Accelerated Research Therapeutics (START) in San Antonio. “Many tumor types lack a robust standard-of-care option, and our results indicate that this class of drug may be efficacious in a variety of cancer types.”

First, the researchers evaluated the efficacy of the three FDA-approved CDK4/6 inhibitors in a panel of 100 breast cancer models. These models, which were derived from breast cancer patients, encompassed all known subtypes of breast cancer and spanned the treatment spectrum, from patients who did not receive any chemotherapy (chemo-naïve) to heavily treated patients, noted Wick.

The researchers tested efficacy by measuring percentage tumor growth. They defined the models as being sensitive if the average tumor growth in the treatment group was 20 percent or less of the average tumor growth observed in the control group following treatment with CDK4/6 inhibitors.

The researchers observed that the HR-positive PDX models derived from chemo-naïve patients were the most sensitive to treatment with CDK inhibitors. Among the HR-positive models evaluated, the researchers observed differential sensitivity to the CDK inhibitors in ESR1-mutant and PIK3CA-mutant breast cancers. The researchers also observed sensitivity to CDK inhibitors in several HR-negative models of breast cancer.

“The finding that HR-negative breast cancer could be sensitive to CDK inhibition is exciting, as it provides a rationale for further investigation of this class of drug beyond HR-positive breast cancers,” said Wick.

The team then expanded this analysis to a variety of different solid malignancies. Sensitivity to palbociclib varied among cancer types, with 60 percent of gastric cancer PDX models being sensitive, followed by colorectal cancer (45 percent), renal cancer (45 percent), melanoma (40 percent), head/neck cancer (35 percent), pancreatic cancer (30 percent), ovarian cancer (15 percent), and lung cancer (10 percent).The researchers also evaluated tumor regressions following treatment with palbociclib and found partial responses in PDX models of ovarian cancer, pancreatic cancer, head/neck cancer, renal cancer, colorectal cancer, and melanoma. They observed one complete response following palbociclib treatment in a PDX model of lung cancer.”Based on our results, we believe that CDK inhibition may be a viable therapeutic option in a host of different cancer types, especially in combination with existing therapies,” said Wick. “We are actively investigating if the addition of clinically available drugs to CDK inhibitors can cause additive results in our PDX models.”

Wick noted that these are preclinical models that require further evaluation before translation into the clinic.

This study was sponsored by START. Wick declares no conflicts of interest.