Simultaneous Targeting of CDK4/6 and BETs is Independent of RB Status in Osteosarcoma
type: CreativeWork
description: Osteosarcoma (OS), the third most common malignancy in adolescents, is characterized by heterogeneity and genomic instability. Despite aggressive multimodal therapy, survival rates remain around 60% for localized and between 5-30% for metastatic disease. OS has a high propensity for early hematogenous and recurrence, indicating a critical need for novel treatment options. Genomic analysis from the Pediatric Cancer Precision Genomics Program at our institution and others have identified dysregulation in replication stress (RS) pathways (MYC, RAD21) and cell cycle regulators (CDKN2A, CDK4/6), pointing to CDK4/6 inhibitors (CDK4/6i), like palbociclib and abemaciclib, as promising therapeutic strategies. However, monotherapy often fails, highlighting the need for effective combination approaches. While functional RB has traditionally been viewed as necessary for CDK4/6i sensitivity, emerging evidence challenges this paradigm and suggests that RB-deficient (RB-) tumors may respond through alternative, RB-independent mechanisms. Bromodomain and extraterminal (BET) proteins are targeted by BET inhibitors (BETi), like AZD5153, are epigenetic readers that regulate the transcription of oncogenes like MYC, E2F and mTOR, and increase transcription-replication errors promoting genomic instability, complementing CDK4/6 blockade. Based on functional in vitro drug screens in the Pollok lab, my dissertation investigates whether combining CDK4/6i with a BETi enhances therapeutic efficacy regardless of RB status. My research demonstrates that dual BETi and CDK4/6i therapy produces additive-to-synergistic anti-tumor effects in both RB-proficient (RB+) and RB- OS cell lines, including CRISPR-engineered RB-knockout clones. Functional studies show enhanced apoptosis, DNA damage, altered cell cycle progression, and reduced clonogenicity. In vivo, combination therapy significantly suppressed tumor growth in both treatment-naïve and previously treated OS patient-derived xenograft models. In …
abstract: Osteosarcoma (OS), the third most common malignancy in adolescents, is characterized by heterogeneity and genomic instability. Despite aggressive multimodal therapy, survival rates remain around 60% for localized and between 5-30% for metastatic disease. OS has a high propensity for early hematogenous and recurrence, indicating a critical need for novel treatment options. Genomic analysis from the Pediatric Cancer Precision Genomics Program at our institution and others have identified dysregulation in replication stress (RS) pathways (MYC, RAD21) and cell cycle regulators (CDKN2A, CDK4/6), pointing to CDK4/6 inhibitors (CDK4/6i), like palbociclib and abemaciclib, as promising therapeutic strategies. However, monotherapy often fails, highlighting the need for effective combination approaches. While functional RB has traditionally been viewed as necessary for CDK4/6i sensitivity, emerging evidence challenges this paradigm and suggests that RB-deficient (RB-) tumors may respond through alternative, RB-independent mechanisms. Bromodomain and extraterminal (BET) proteins are targeted by BET inhibitors (BETi), like AZD5153, are epigenetic readers that regulate the transcription of oncogenes like MYC, E2F and mTOR, and increase transcription-replication errors promoting genomic instability, complementing CDK4/6 blockade. Based on functional in vitro drug screens in the Pollok lab, my dissertation investigates whether combining CDK4/6i with a BETi enhances therapeutic efficacy regardless of RB status. My research demonstrates that dual BETi and CDK4/6i therapy produces additive-to-synergistic anti-tumor effects in both RB-proficient (RB+) and RB- OS cell lines, including CRISPR-engineered RB-knockout clones. Functional studies show enhanced apoptosis, DNA damage, altered cell cycle progression, and reduced clonogenicity. In vivo, combination therapy significantly suppressed tumor growth in both treatment-naïve and previously treated OS patient-derived xenograft models. In …
author: Malko, Rada
language: en_US
keywords: CDK4/6, Cell Cycle, Combination therapy, Osteosarcoma, Sarcoma, Targeted Therapy
date published: 2026-03
date modified: 2026-07-24T02:42:13Z
provider: IUPUI
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: IUPUI

PropertyValue
property ID: Handle
value: https://hdl.handle.net/1805/55154