Monopolar Spindle 1, or MPS1, is a protein kinase with a fundamental role in cell division. As a member of the serine/threonine kinase family, it functions by adding phosphate groups to other proteins to alter their activity. It is important to distinguish MPS1 from the genetic disorder Mucopolysaccharidosis type I (MPS I), an entirely different condition. The primary function of MPS1 is to ensure that genetic material is duplicated and sorted correctly when a cell divides, a process foundational to tissue growth.
MPS1’s Role in Cell Division
Every time a cell replicates, it undergoes an organized sequence of events called the cell cycle, which culminates in mitosis. During this phase, one cell divides into two identical daughter cells, and a central challenge is the accurate segregation of chromosomes. Each new cell must receive a complete set of chromosomes to function properly, so cells use a quality control system called the Spindle Assembly Checkpoint (SAC).
The SAC acts as a surveillance mechanism, halting cell division until it confirms that every chromosome is properly attached to a structure called the mitotic spindle. The spindle is a scaffold of protein filaments, called microtubules, that pull the duplicated chromosomes apart. MPS1 functions as a regulator within the SAC, acting as a primary sensor at the kinetochores, the protein structures on chromosomes where microtubules attach.
When a kinetochore is not correctly attached to microtubules, MPS1 is activated and initiates a signaling cascade. This signal prevents the cell from entering anaphase, the final stage of division where chromosomes are irreversibly separated. In this capacity, MPS1 acts as an inspector on a cellular assembly line, holding production until it verifies that chromosome attachment is complete, thereby ensuring the fidelity of genetic inheritance.
Consequences of MPS1 Dysregulation
When the regulatory function of MPS1 is compromised, the cell’s quality control system for division fails. A malfunctioning MPS1 cannot properly detect unattached chromosomes, leading to a premature silencing of the Spindle Assembly Checkpoint. This failure allows the cell to proceed with division before all chromosomes are securely captured by the mitotic spindle, resulting in an uneven distribution of genetic material.
This erroneous chromosome segregation leads to a state known as aneuploidy, an abnormal number of chromosomes. A daughter cell might end up with extra copies of some chromosomes or be missing others entirely. This imbalance disrupts the normal dosage of many genes, leading to an unstable cellular environment that impairs the ability of normal cells to function and proliferate.
The Connection Between MPS1 and Cancer
The presence of aneuploidy is a hallmark of cancer, with the majority of human tumors exhibiting an abnormal number of chromosomes. This creates a paradox: if aneuploidy is inherently destabilizing, how do cancer cells not only survive but thrive in this state? The answer often involves MPS1. Many aggressive tumors, including those in breast, colon, and pancreatic cancers, have been found to overexpress MPS1, producing it at significantly higher levels than healthy tissues.
This overexpression of MPS1 helps cancer cells manage their chromosomal instability. While the high rate of chromosome missegregation helps tumors evolve and gain aggressive traits, it also risks causing fatal errors that would lead to cell death. The elevated levels of MPS1 provide a buffer, strengthening the Spindle Assembly Checkpoint just enough to prevent these fatal segregation errors without correcting the underlying instability.
This reliance creates a dependency referred to as non-oncogene addiction, where a cancer cell becomes dependent on a protein that is not a classic cancer-causing gene. The tumor’s survival is intricately linked to the continued overexpression of MPS1, which helps it tolerate a level of genetic chaos that would be lethal to a normal cell. This addiction makes MPS1 a unique vulnerability in cancer cells.
Targeting MPS1 for Cancer Therapy
The discovery that many cancer cells are addicted to high levels of MPS1 has opened a new avenue for therapeutic intervention. The strategy is based on the principle of synthetic lethality, where blocking MPS1 function selectively harms cancer cells due to their unique dependency. This has led to the development of a class of drugs known as MPS1 inhibitors.
These small-molecule inhibitors are designed to fit into the active site of the MPS1 protein, blocking its ability to phosphorylate other proteins and shutting down its function. By inhibiting MPS1, these drugs disable the Spindle Assembly Checkpoint. In aneuploid cancer cells, this inhibition triggers severe mitotic errors, leading to widespread chromosome missegregation and cell death. Healthy cells are better able to tolerate the temporary loss of this checkpoint.
Several MPS1 inhibitors have been developed and are being evaluated in clinical trials for various solid tumors, including breast and pancreatic cancer. Some trials are exploring these inhibitors as standalone treatments, while others are testing them in combination with existing cancer therapies like paclitaxel, a drug that also affects the mitotic spindle.