# Project 1: Therapeutic targeting  of CDK4 in Mantle Cell Lymphoma

> **NIH NIH P01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $332,424

## Abstract

Mantle cell lymphoma (MCL) remains incurable due to the development of drug resistance despite advances in
targeted therapy. Each successive treatment failure is associated with a more rapidly proliferating disease and
fewer practical treatment options. For example, the BTK inhibitor (BTKi) ibrutinib has unprecedented activity
but failure is virtually universal and is associated with dismal outcomes. Understanding the mechanism and
genomic basis for therapy resistance is thus fundamental to developing superior durable therapies that are
also amenable to patient stratification in MCL. As dysregulation of CDK4 (CDK6 is not expressed in MCL) and
aberrant cyclin D1 expression underlie MCL proliferation, targeting CDK4 represents a rational approach to
developing novel therapies that circumvent ibrutinib resistance in MCL. We have previously demonstrated that
the clinical response to ibrutinib was tightly associated with PI3K inactivation in MCL patients. Induction of
prolonged early G1 arrest (pG1) by inhibiting CDK4 with palbociclib (selective CDK4/6 inhibitor) restricts the
expression of genes to those scheduled for early G1 only. This led to an imbalance in gene expression that
reprogrammed MCL cells for therapeutic vulnerability, including BTK and PI3K inhibition. On this basis, we
hypothesize that targeting CDK4 will both restrict the expansion of resistant clones and reprogram MCL cells
for a deeper, and more durable clinical response to BTKi or PI3Ki. Supporting this hypothesis, our phase I
clinical trial of palbociclib in combination with ibrutinib for patients with recurrent MCL (PALIBR) revealed a
promising 67% overall response rate with 43% complete response (N=27), Moreover the response was rapid
and durable; only 14% responding patients have progressed in ~32 months since the trial opened. Capitalizing
on these exciting findings and the upcoming phase 2 PALIBR clinical trial, we propose to define the
mechanism of pG1 reprograming for therapeutic vulnerability and the molecular biomarkers that discriminate
sensitivity from resistance to targeting CDK4 in MCL with two specific aims: 1) to determine the genomic basis
for resistance to targeting CDK4 in combination therapy. We will determine if composite copy number variation
(CNV) and clonal selection causes resistance to PALIBR by longitudinal functional genomics and develop
strategies to circumvent PALIBR resistance by targeting the therapeutic vulnerability conferred by resistance
biomarkers; 2) to elucidate the mechanism for pG1 reprogramming in MCL cells. We will test our hypothesis
that by reinforcing Rb sequestration of E2F1, CDK4 inhibition disrupts the E2F1- EZH2 regulatory circuitry,
which sustains the pG1 state needed for a durable clinical response and reprograms MCL cells for therapy
vulnerability through chromatin remodeling, repression of IRF4 and inactivation of PI3K. Targeting CDK4/6 is
now FDA-approved for treatment of breast cancer and is being actively investigated in di...

## Key facts

- **NIH application ID:** 10478981
- **Project number:** 5P01CA214274-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** SELINA Y CHEN-KIANG
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $332,424
- **Award type:** 5
- **Project period:** 2018-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478981

## Citation

> US National Institutes of Health, RePORTER application 10478981, Project 1: Therapeutic targeting  of CDK4 in Mantle Cell Lymphoma (5P01CA214274-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10478981. Licensed CC0.

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