Sequential Targeting of Retinoblastoma and DNA Synthesis Pathways Is a Therapeutic Strategy for Sarcomas That Can Be Monitored in Real Time

Authors

Tuyen Duong Thanh Nguyen
Yan Wang
Tuyen N Bui
Rossana Lazcano
Davis R Ingram
Min Yi
Varshini Vakulabharanam
Linjie Luo
Marc A Pina
Cansu Karakas
Mi Li
Nicole M Kettner
Neeta Somaiah
Peter J Hougton
Osama Mawlawi
Alexander J Lazar
Kelly K Hunt
Khandan Keyomarsi

Publication Date

3-15-2023

Journal

Cancer Research

Abstract

Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell-cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1,043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective two-step sequential combination strategy was developed. Abemaciclib was used first to prime Rb-positive sarcoma cells to reversibly arrest in G1 phase. Upon drug removal, cells synchronously traversed to S phase, where a second treatment with S-phase targeted agents (gemcitabine or Wee1 kinase inhibitor) mediated a synergistic response by inducing DNA damage. The response to treatment could be noninvasively monitored using real-time positron emission tomography imaging and serum thymidine kinase activity. Collectively, these results show that a novel, sequential treatment strategy with a CDK4/6 inhibitor followed by a DNA-damaging agent was effective, resulting in synergistic tumor cell killing. This approach can be readily translated into a clinical trial with noninvasive functional imaging and serum biomarkers as indicators of response and cell cycling.

Keywords

CDK4/6 inhibitor, soft tissue sarcomas, biomarkers, functional imaging, sequential combination treatment

Comments

Supplementary Material

PMID: 36603130

DOI

10.1158/0008-5472.CAN-22-2258

PMID

36603130

PMCID

PMC10023441

PubMedCentral® Posted Date

September 2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes