RB1, Cancer Lineage Plasticity, and Therapeutic Resistance

Lineage plasticity, a cell's capacity to switch lineage-restricted gene expression states, is required for normal tissue homeostasis. Cancer lineage plasticity is increasingly observed as a mechanism of resistance to therapy, particularly molecularly targeted therapies. These therapies often owe their superior efficacy to the lineage-restricted nature of their therapeutic target, so cancers can evade such therapies by changing lineage states. As increasingly effective molecularly targeted therapies are deployed, cancer lineage plasticity is likely to be a growing clinical problem. Lineage plasticity reflects a nongenetic, potentially reversible transcriptional adaptation, but oncogenic genetic mutations likely drive elevated lineage plasticity that is typical of cancer cells. Here key concepts relevant to cancer lineage plasticity are presented, evidence implicating loss of the RB1 tumor-suppressor gene in driving cancer lineage plasticity is reviewed, and possible therapeutic approaches to counter cancer lineage plasticity are discussed.