ONC201 Mechanism of Action: How It Targets Cancer Cells

ONC201 is an investigational anti-cancer drug undergoing clinical trials for various advanced malignancies, including brain tumors with specific genetic mutations. This orally administered small molecule belongs to a new class of compounds called imipridones. The drug’s mechanism of action involves targeting specific pathways within cancer cells, leading to their selective elimination.

The Primary Target: Dopamine Receptor D2

One of ONC201’s primary actions involves the Dopamine Receptor D2 (DRD2), a G protein-coupled receptor found on the surface of cells. DRD2 typically plays a role in regulating various cellular processes, including signaling pathways that influence cell growth and survival. ONC201 acts as a selective antagonist of DRD2, meaning it binds to the receptor and blocks its normal activity.

By antagonizing DRD2, ONC201 disrupts specific signaling cascades often hyperactive in cancer cells, such as the ERK (extracellular signal-regulated kinase) signaling pathway. This disruption contributes to the drug’s anti-cancer effects by interfering with the abnormal growth signals that drive cancer progression. While DRD2 antagonism is a significant part of ONC201’s action, it is not the sole mechanism by which the drug exerts its anti-cancer activity. Some studies suggest that ONC201’s effects extend beyond its interaction with DRD2, indicating additional pathways are involved.

The Mitochondrial Target: ClpP Protease

ONC201 also interacts with the mitochondrial caseinolytic protease P (ClpP), a protein located within the mitochondria. ClpP normally functions in maintaining mitochondrial health by degrading misfolded or damaged proteins. ONC201 directly binds to and activates ClpP, increasing its proteolytic activity.

This hyperactivation of ClpP by ONC201 leads to the degradation of essential mitochondrial proteins, including some necessary for energy production. The resulting disruption in protein homeostasis and impaired oxidative phosphorylation causes mitochondrial dysfunction and stress within the cell. This unique interaction with ClpP represents a distinct contribution to ONC201’s overall mechanism, leading to energy depletion and ultimately cell death in cancer cells.

How ONC201 Selectively Impacts Cancer Cells

ONC201 exhibits a selective impact, primarily affecting cancer cells while largely sparing healthy cells. This selectivity can be attributed to several factors that exploit the inherent vulnerabilities of cancerous cells. Some cancer cells, particularly those found in certain brain tumors, exhibit higher expression levels of DRD2, making them more susceptible to ONC201’s antagonistic effects.

Cancer cells often rely heavily on specific signaling pathways, like the ERK pathway, for their uncontrolled growth and survival. By disrupting these pathways through DRD2 antagonism, ONC201 disproportionately affects cancer cells that are highly dependent on them. Cancer cells generally have altered metabolism and rapid proliferation rates, making them more vulnerable to the mitochondrial stress induced by ClpP activation. The integrated stress response (ISR), a cellular pathway triggered by various stresses, appears to be more easily activated or more detrimental in cancer cells, contributing to their demise upon ONC201 treatment.

Cellular Consequences of ONC201 Action

The combined actions of ONC201, through both DRD2 antagonism and ClpP activation, lead to downstream consequences within cancer cells. The disruption of DRD2 signaling, coupled with the hyperactivation of ClpP, results in mitochondrial dysfunction and depletion of cellular energy. This energy starvation impairs the cancer cell’s ability to maintain its rapid growth and survival.

A key outcome is the activation of the integrated stress response (ISR). This response involves the upregulation of specific transcription factors, such as ATF4 and CHOP, which then regulate genes involved in stress adaptation and programmed cell death. The activation of the ISR, along with the disruption of protein synthesis and inactivation of pathways like Akt/ERK, induces programmed cell death (apoptosis) in cancer cells. These effects contribute to the elimination of cancer cells.

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