Tyrosine phosphorylation of p27Kip1 as a biomarker to identify Cdk4/6 inhibitor response

SUMMARY
While the CDK4 targeting drugs (CDK4i), Palbociclib, Abemaciclib, and Ribociclib, have shown clinical promise
in the treatment of metastatic breast cancer (BC), lack of a companion diagnostic to identify responsive
patients remains a problem. While CDK4i therapy increases progression-free survival (PFS) in some
metastatic HR+ patients, many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any
benefit from these agents, switching to chemotherapy within 6 months. Development of a biomarker to identify
the presence of the active CDK4 target, and therefore CDK4i sensitive patients, would enable responsive
metastatic breast cancer patients to be pinpointed at the onset of therapy. As CDK4/6 is downstream of all
oncogenic signaling pathways, it is also likely that this class of drugs will have efficacy in at least a subset of
additional tumor types, and a biomarker for CDK4i responsiveness would accelerate the expansion of this
class of therapy into tumor types, such as metastatic Her2+, Triple negative breast or ovarian cancer, which
have few therapeutic options. A biomarker to predict effectiveness of CDK4i would mean more rapid benefit to
the correct patients, a cost and time savings and reduced toxicity for patients who would not be benefited and
extended use of these therapies across tumor types where novel therapies are desperately needed. In
essence: a biomarker would help get the right drug to the right patients. This translational project will focus on
the utility of a novel diagnostic marker, p27Kip1 pY88, to identify patients who would respond to the currently
used CDK4i therapy. In published and presented work, we have shown that pY88 serves as a surrogate
marker for CDK4 activity and in turn CDK4i responsiveness, in cell lines, primary explant culture, and now in
biopsies from patients treated clinically with CDK4i therapy. The goal of this RO1 project is to demonstrate
that p27 pY is a diagnostic biomarker to identify CDK4/6i-responsive patients and then also to
reconcile why pY might demarcate resistance by associating it to mechanisms of resistance, with the
idea that this will further inform potential uses of the CDK4/6i drugs. In Aims 1 and 2 (translational aims) we
plan to test an IHC based assay to determine if pY88 can serve as a biomarker to predict significant PFS
improvement in patients with HR+/HER2- BC treated with CDK4/6i. In Aim 3 (mechanism aim), we will
determine how pY status relates to CDK4/6i sensitivity and resistance. Aim 1: To test the ability of the pY
biomarker to predict significant PFS, by comparing pY88 status in biopsy material from patients with HR+
BC treated clinically with CDK4/6i with patient outcome data. Aim 2. To test the validated pY test in
clinically relevant cohorts, from two completed and ongoing clinical trials. Aim 3: To determine how pY
status relates to CDK4/6i sensitivity and resistance, by using biochemical studies to examine pY status in
in vitro and in vivo models of CDK4/6i resistance.

Grant Number: 5R01CA249667-04
NIH Institute/Center: NIH
Principal Investigator: JANICE BRISSETTE