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

Abstract

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.

Keywords: CDK4; E2F; EZH2; RB1; cyclin; epigenetics; immunotherapy; palbociclib; retinoblastoma.

Figure 1.. Canonical RB1-pathway:

In the canonical pathway mitogenic signals lead to the activation of CDK4/6 complexes with D-type cyclins. These kinases initiate the phosphorylation and inactivation of the retinoblastoma tumor suppressor, thereby leading to the de-repression of E2F regulated genes. These proliferative signals can be antagonized by multiple anti-proliferative signals which can directly limit the activation of CDK4/6 or induce the expression of endogenous inhibitors exemplified by p16ink4a.

Figure 2.. Deepening cell cycle exit with combination therapies:

While the RB1-pathway is generally considered linear, the activity of both CDK4/6 and CDK2 can be induced by oncogenic signaling pathways. In the context of CDK4/6 inhibition, there can be adaptive upregulation of both cyclin D1 and cyclin E. These processes are linked to oncogenic signaling and can be ameliorated by productive combination therapies with agents targeting different signaling pathways. The basis for this cooperation is believed to involve the inhibition of CDK2 activity and maintenance of RB1 activity.

Figure 3.. Distinct forms of genetic heterogeneity that drive RB1 loss with therapeutic selection:

In the presence of different cytostatic therapies, there is a selective pressure for tumors that have lost RB1. This selection can allow for enrichment of pre-existing subclonal mutations or provide the basis for selection of de novo RB1 mutations. Tumors that are deficient in RB1 have been shown to be selectively sensitive to agents that target DNA-replication (CHK1 inhibitors) and mitotic segregation (PLK1 and AURK inhibitors).

Figure 4.. Impact of RB-pathway on tumor immunology and the tumor microenvironment:

CDK4/6 inhibition and the activation of RB1 can lead to cell cycle inhibition in the tumor and tumor cell intrinsic effects relative to antigen presentation (e.g. MHC expression), interferon response (e.g. cytokine release). These events can enhance the mobilization of immune cells and NK cells into the tumor microenvironment. In parallel with these effects, the CDK4/6 inhibition has critical effects on T-regulatory cells, Myeloid-derived suppressors, and T-effector cells that have distinct effects on tumor biology.

Figure 5.. Impact of the RB1 pathway on cancer lineage plasticity and acquired therapeutic resistance.

The figure depicts the increasingly appreciated effects of RB1 on epigenetic instability mediated by the cell cycle and pluripotency regulatory networks aberrantly re-activated in cancer. This epigenetic instability can facilitate adaptation of cancer cells to therapies targeting lineage specific dependencies (e.g. androgen receptor, EGFR, etc.). Points of possible therapeutic intervention to counter cancer lineage plasticity include activation of the RB1 when it is present or suppressing downstream effects of RB1 loss using epigenetic modulating drugs.