The Story of FGFR1

Mutations within FGFR 1 are linked to many cancers, but each alteration may have its own unique effect on a tumor.

In the early 1970s, scientists trying to understand how different organs control growth performed a simple test: they grew cells from connective tissue, known as fibroblasts, using extracts from tissues such as cow brains or the pituitary glands of mice.

Under the microscope, they watched the fibroblasts – stretchy cells with finger-like extensions – divide and grow under the influence of a previously unknown growth factor from the brain and pituitary. Since the substance spurred fibroblasts to multiply, this small protein was dubbed fibroblast growth factor (FGF).

Later, this growth factor was found to influence more than just fibroblasts. In fact, all our cells carry genes known as FGF-receptors, or simply FGFRs, that allow many cells in the body to respond to tiny chemical triggers by multiplying. FGFR1 is a gene that produces proteins that are part of the FGFR family of receptors, all of which are tuned to respond to growth-stimulating proteins in different ways.

Much like fibroblasts in a laboratory dish, cells in the body are bathed in fluids that carry chemical messages from distant organs. FGFR1 helps cells interpret these cues. The FGFR1 gene makes a protein of the same name, which bridges the cell membrane. The FGFR1 protein listens for signals from outside the cell and responds by initiating chemical cascades inside cells that make them multiply. Depending on where it functions, cells respond to FGFR1 by reproducing, spreading out to new locations, or forming new blood vessels to feed growing tissues.

When FGFR1’s machinery goes awry, these same functions wreak havoc: they can make tumors grow and the blood vessels that nourish them grow and spread.

Since the FGFR1 protein is found in so many different tissues, a faulty gene can trigger cancer in any of several different locations. FGFR1 malfunctions have been linked to cancers of the lung, head and neck, bladder, breast, prostate, stomach, and squamous cell carcinoma in the mouth and esophagus.

But what causes such an important gene to stop working properly? Errors can creep in at many levels. A gene is simply a string of chemical letters, much like a word written in the language of DNA. Like a typo, a mistake in the letters that compose a gene can spell trouble. Such errors in the FGFR1 gene sequence, known as somatic mutations, have been spotted in some cases of breast and lung cancer.

In healthy cells, the FGFR1 gene lies on the shorter arm of chromosome 8, at a location dubbed 8p11. Some cancers originate when the chunk of DNA encoding this gene gets “translocated” or moved to a different part of the genome. Such rearrangements activate the FGFR1 gene at improper times, pushing cells to multiply in cancers such as acute myelomonocytic leukemia (AMMoL).

In other cases, the chunk of DNA that carries the gene can be “amplified,” or repeated multiple times. Think of it as a word being copy-and-pasted too many times, so it is then read too many times. When the FGFR1 gene is amplified in this way, it can make too much of its own RNA and protein. Twenty percent of patients with lung squamous cell carcinomas and up to 43 percent of patients with lobular carcinomas in the breast carry FGFR1 amplifications in their tumors. Even without being amplified, many tumors carry an FGFR1 gene that is over-active and makes too much of its own RNA and protein. This over-expression is particularly common in lung cancer and head and neck cancers.

Individually, each of these errors – mutations, making too much RNA and protein, or carrying too many copies of a gene – is unique. But all make for a dysfunctional FGFR1, and result in cancers across many

In the last decade, scientists have found that when FGFR1 is amplified or over-expressed in tumors, it is usually associated with a poorer prognosis. In breast cancer patients, FGFR1 amplifications have also been linked to drug resistance; tumors with these mutations may be less likely to respond to hormone-based medicines. So far, there’s not much evidence to suggest that FGFR1 can make cancers grow faster or spread more quickly. However, clinical tests for FGFR1 errors can help pinpoint if a cancer is resistant to certain therapies, for example, to identify resistance to the chemotherapy drug imatinib (trade name, Gleevec) in leukemia.

Since errors in FGFR1 are so widespread, the gene is considered a promising, high-priority target to design new medicines against. Although many small molecule inhibitors have been tested on cell lines and animal models with FGFR1 aberrations, only a few, such as dovitinib, have been tested in clinical trials. These studies are yet to yield any unequivocally promising candidates. Why is it so difficult to fix a faulty FGFR1 gene or protein?

One reason researchers have found is that not all FGFR1 defects are equal in their cancerous effects. A cell with too many copies of the chromosome chunk that carries FGFR1 does not behave in the same way as a tumor that spews too much FGFR1 RNA and protein. Amplification, or having too many copies of the gene, appears to correlate with making more RNA copies in breast cancer, but not in lung cancer. As a result, testing a drug that targets FGFR1 expression on cancers with an amplified gene can produce mixed results: If amplification and expression are linked, the drug may prove effective. But if not, it might appear as though the drug is ineffective.

It’s possible that teasing apart the different kinds of FGFR1 defects will help tailor such medicines better to each malfunction and type of cancer. In an ongoing trial, for example, researchers are trying to understand how lung cancer patients with an amplified FGFR1 gene and individuals with increased expression of FGFR1 in their tumors may respond differently to treatments.

As scientists learn about the unique traits of each FGFR1 defect in different cancer types, they can design “stratified trials,” where patients can receive treatments tailored to the genetic profile of their individual cancer. Testing for FGFR1 gene defects in different cancers is a first step to answering the question of how to correct faults in this gene’s function.

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