Cell Cycle and Beyond: Exploiting New RB1 Controlled Mechanisms for Cancer Therapy

Sensitivity to CDK4/6 inhibitors can be expanded by ameliorating cell cycle plasticity and deepening cell cycle exit with combination therapies. Targeting the vulnerabilities of tumors lacking RB1 provides a new precision means to attack tumors that escape cytostatic interventions. RB1 pathway activation in normal tissue can limit the adverse effects of specific therapeutic interventions and provides a means to expand the therapeutic index against RB1-deficient tumors. Exploiting the impact of RB1 on immunological features of the tumor compartment and microenvironment can expand sensitivity to immunotherapy and provides hope for yielding highly durable combinatorial therapies. Understanding the disparate roles of RB1 in coordinating epigenetic states that drive histological transformation and resistance to targeted therapies will provide new opportunities to prevent resistance and intercede in advanced disease. Recent studies highlight the importance of the RB1 tumor suppressor as a target for cancer therapy. Canonically, RB1 regulates cell cycle progression and represents the downstream target for cyclin-dependent kinase (CDK) 4/6 inhibitors that are in clinical use. However, newly discovered features of the RB1 pathway suggest new therapeutic strategies to counter resistance and improve precision medicine. These therapeutic strategies include deepening cell cycle exit with CDK4/6 inhibitor combinations, selectively targeting tumors that have lost RB1, and expanding therapeutic index by mitigating therapy-associated adverse effects. In addition, RB1 impacts immunological features of tumors and the microenvironment that can enhance sensitivity to immunotherapy. Lastly, RB1 specifies epigenetically determined cell lineage states that are disrupted during therapy resistance and could be re-installed through the direct use of epigenetic therapies. Thus, new opportunities are emerging to improve cancer therapy by exploiting the RB1 pathway. Recent studies highlight the importance of the RB1 tumor suppressor as a target for cancer therapy. Canonically, RB1 regulates cell cycle progression and represents the downstream target for cyclin-dependent kinase (CDK) 4/6 inhibitors that are in clinical use. However, newly discovered features of the RB1 pathway suggest new therapeutic strategies to counter resistance and improve precision medicine. These therapeutic strategies include deepening cell cycle exit with CDK4/6 inhibitor combinations, selectively targeting tumors that have lost RB1, and expanding therapeutic index by mitigating therapy-associated adverse effects. In addition, RB1 impacts immunological features of tumors and the microenvironment that can enhance sensitivity to immunotherapy. Lastly, RB1 specifies epigenetically determined cell lineage states that are disrupted during therapy resistance and could be re-installed through the direct use of epigenetic therapies. Thus, new opportunities are emerging to improve cancer therapy by exploiting the RB1 pathway.