BP9. Non-Genetic Mechanisms of Fractional Resistance to Abemaciclib in Dedifferentiated Liposarcoma

Friday, March 6, 2026

8:58 AM - 9:05 AM MST

Location: 301A

Primary Presenter(s)

Lauryn E. Bailey, BS

Graduate Research Specialist
UNC Chapel Hill School of Medicine, Department of Genetics
Chapel Hill, North Carolina, United States

Slides

Primary Author(s)

Sam Wolff, PhD (he/him/his)

Assistant Professor
UNC Chapel Hill School of Medicine, Department of Genetics
Chapel Hill, North Carolina, United States

Co-Author(s)

Tarek M. Zikry, PhD

Assistant Professor
UNC Chapel Hill School of Data Science and Society
Chapel Hill, North Carolina, United States
GS

Garrett A. Sessions, n/a

Graduate Student
UNC Chapel Hill School of Medicine, Department of Cell Biology and Physiology
Durham, North Carolina, United States
AW

Austin Whitman, n/a

Research Specialist
UNC Chapel Hill School of Medicine, Department of Surgery
Chapel Hill, North Carolina, United States
Elizaveta K. Titerina, MD (she/her/hers)

Postdoctoral Scholar
Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University
Columbus, Ohio, United States
HR

Hayden Raish, n/a

Research Specialist
Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University
Columbus, Ohio, United States
Joal D. Beane, MD

Assistant Professor
Department of Surgery, The Ohio State University Wexner Medical Center
Columbus, Ohio, United States
JP

Jeremy Purvis, PhD

Professor
UNC Chapel Hill School of Medicine, Department of Genetics
Chapel Hill, North Carolina, United States

Primary Author(s)

Philip M. Spanheimer, MD (he/him/his)

Associate Professor
University of North Carolina, Department of Surgery
Chapel Hill, North Carolina, United States

Co-Author(s)

Lauryn E. Bailey, BS

Graduate Research Specialist
UNC Chapel Hill School of Medicine, Department of Genetics
Chapel Hill, North Carolina, United States

Slides

Introduction: Well/dedifferentiated liposarcomas overexpress CDK4 but clinical trials of CDK4/6 inhibitors (CDK4/6i) have had mixed results. We hypothesized that fractional resistance arises from phenotypic plasticity that enables continued cell division in a fraction of cells under CDK4/6i. Our objective was to use cell lines and primary tumor cells to characterize aberrant cell cycle regulation representing alternative paths to cell division despite CDK4/6i.

Methods: Iterative indirect immunofluorescence imaging (4i, Fig A) was performed on liposarcoma cell line 246 and primary patient-derived de-differentiated liposarcoma cells treated with the CDK4/6i abemaciclib (0, 50, 250 nM), profiling 17 regulators of cell cycle proliferation in individual cells. Cycling cells were computationally isolated by stratifying for high pRb/Rb and cycling cells off treatment compared to cycling cells on treatment to determine unique features of fractional resistance.

Results: Proliferating cells were identified by high pRb/Rb ratio (Fig B). The fraction of cells proliferating reduced with abemaciclib treatment in a dose dependent fashion from 92.3% control to 81.5% 50 nM to 5.1% 250 nM, p< 0.001, demonstrating on target arrest inducing effects, and a discrete pRb/Rb high subset that persisted on treatment (fractional resistance). Within fractionally resistant cells (Red), CDK2 expression increased from median z-normalized signal intensity 0.38 in control treated cycling cells to -0.26 (abemaciclib 50 nM) and 1.60 (abemaciclib 250 nM), p< 0.001. The G2/M phase regulating cycB1 had a significant induction of expression with 250 nM abemaciclib treatment (median z-normalized signal intensity -0.27 control to 2.67 250 nM) p< 0.0001. Neither CDK2 nor cycB1 changed expression in arrested cells with abemaciclib treatment. Representative IF images demonstrate co-localization of persistent pRb high cells with abemaciclib treatment and high expression of CDK2 and cycB1. Fractionally resistant primary tumor cells showed similar increase in cycB1 ( -0.37 control vs -0.19 250 nM abemaciclib, p< 00.1) and CDK2 (-0.25 control vs 0.46 250 nM abemacilib, p< 0.001).

Conclusions: Dedifferentiated liposarcoma cells that escape abemaciclib induced arrest have increased expression of CycB1 and CDK2 supporting an abemaciclib resistant cell cycle path driven by non-canonical activation of CDK2 by CycB1. Future studies will focus on CycB1 and CDK2 as biomarkers of patients with dedifferentiated liposarcoma least likely to respond to CDK4/6 inhibitors and on co-treatment strategies targeting CDK2.

Learning Objectives:

Define fractional resistance as a persistent, proliferative subpopulation that endures therapy through adaptive cell states, and recognize this phenomenon in diverse experimental and clinical contexts.
Describe how cell-to-cell plasticity generates alternate proliferative trajectories under CDK4/6 inhibition, including the non-canonical cyclin B1–CDK2 activation revealed in liposarcoma single-cell data.
Evaluate how an OR-to-lab single-cell analysis workflow links patient tumor samples to high-dimensional molecular profiles, enabling clinical-to-research pipelines for patient-specific biomarker development and treatment planning.