Gene mutation that causes head and neck cancer could serve as precise therapeutic target

Keys to targeting this vulnerability include individualized genomic analysis to identify a patient's specific mutation and find a way to directly target that mutation, they report in a review article in the journal NPJ Genomic Medicine.

The MAPK pathway is a "signaling hub" for cells important for normal head and neck development, activating key pathway components, such as the genes MAPK1 and HRAS, which are known to drive the growth of various cancers, said Dr.

But mutations in the genes in the MAPK pathway that make tumors grow can also make them susceptible to drug treatment, Lui said

As she speaks, she is in her lab searching for drugs that can kill primary tumors in patients' heads and necks, and the genetics behind how they kill tumors

"This is critical for cancer survival," and each cancer type may have one or more drug-sensitive mutations, which may vary among individuals depending on how the cancer develops

If these types of studies continue to find this approach effective, gene panels may need to be developed to accelerate target discovery in this heterogeneous cancer, the scientists wrote

Globally, more clinical trials at institutions like MCG and the Georgia Cancer Center are critical to pinpoint identification of these specific mutations and drugs to target them, Lui noted

In addition, she said, the next thing on the horizon is combining this "precision medicine" approach with immunotherapy to better enable a patient's immune system to target cancer as well

Lui's interest in the MAPK pathway was cemented nearly a decade ago at the University of Pittsburgh, where she conducted postdoctoral research and eventually became a faculty member

The patients were given erlotinib, a drug that isn't particularly effective against these cancers, but researchers are looking to see if it can suppress the signaling of this factor important for cancer growth

His response, rightly called an "abnormal response," was the first that Lu and her colleagues had found in head and neck cancer, and she had to find out what mutation the drug was targeting in order to make this response possible.

The EGFR gene mutation is a logical choice for his mutation

Lui found no EGFR mutation in the young man's pretreatment biopsy, but reasoned that the mutation must be related to the receptor's signaling network

Later, when they genetically modified it in head and neck cancer cells, the already aggressive cells grew faster, Lui said, a mutation that could be caused by habits like heavy smoking and drinking

Erlotinib actually failed in clinical trials because it wasn't given to the right patients, which is what precision medicine is all about, Lui noted

To move cancer treatment forward, Lui encourages doctors to report these types of "abnormal reactions" when they encounter them, collaborate with scientists to study them, and then conduct clinical trials in due course

For patients, her message is not to give up, because as the tumor is analyzed at a higher level, there may be a mutation that makes their cancer more vulnerable to specific drugs, which she says are "gene-drug responses" that are The focus of her translation work
.

"There are secrets that make cancer vulnerable," Lu said
.
"When cancer cells have an important genetic mutation that they are activating, or cancer cells are addicted to survive, then when you hit that signaling pathway, the cancer cells die or are well controlled
.
"

Before the era of genomic medicine, when scientists began to identify and target specific genetic mutations, "drugs of the non-precision MAPK pathway for head and neck cancer and other cancers were futile," and often "failed" in clinical trials, He and her colleagues wrote
.

While the reasons may be uncertain, they may include the wrong drug targeting specific, problematic mutations, as well as the fact that some MAPK pathway mutations are known to transmit resistance, Lui said
.

Either way, there's a lot of work to be done
.
Today, there are only a handful of drugs that target specific cancer-causing mutations in head and neck cancer, but no effective precision medicine treats about 80 percent of patients, Lui and her co-authors wrote
.

But mounting evidence suggests that targeting specific mutations in the MAPK pathway, such as MAPK1, HRAS, KRAS, and BRAF, is highly effective in these patients
.

For example, the RAS inhibitor tipifarnib received Breakthrough Therapy Designation from the U.
S.
Food and Drug Administration in February 2021 for the treatment of specific recurrent or metastatic hras-mutated head and neck squamous cell carcinomas
.
HRAS is involved in cell growth signaling
.

In addition, studies have shown that EGFR-targeted therapy for metastatic non-small cell lung cancer increases progression-free survival to a median of 18.
9 months, a median overall survival of more than 3 years, and reduces mortality by approximately 52%
.
In 2016, the U.
S.
Food and Drug Administration revised its approval of erlotinib for the treatment of patients with non-small cell lung cancer with specific EGFR mutations
.
In 2020, the FDA approved erlotinib in combination with ramucirumab as a first-line treatment for these cancers
.
Ramucirumab is a monoclonal antibody that binds to receptors for vascular endothelial growth factor (VEGF), which tumors use to grow the blood vessels they need
.
The FDA granted Breakthrough Therapy designation to tipifarnib, a protein inhibitor that, in this case, acts downstream of a mutation in a gene that interferes with HRAS, which is also involved in cell division and the MAPK pathway
.
More than 1.
5 million NSCLC patients are now receiving precision therapy, as researchers continue to examine the initial minority of responders
.

A native of Hong Kong, Lei taught at the Chinese University of Hong Kong before joining MCG in October 2021
.
In 2020, Lui and her colleagues reported that mutations in the MAPK pathway were a factor in about one in five patients with head and neck cancer, and "surprisingly" these mutations were more associated with patient survival than other causes, such as human papillomavirus.
long related
.

Head and neck cancer is typically aggressive, and often the disease and treatment are painful and disfiguring
.
It has a higher risk of suicide compared to other cancers
.
The incidence of head and neck cancer is worldwide, and causes include tobacco and/or alcohol use, air pollutants, sexually transmitted cancer-causing viruses human papillomavirus, and Epstein-Barr virus, one of the most common viruses primarily transmitted through Saliva transmission can cause problems such as infectious mononucleosis
.
Other causes include poor oral hygiene and betel nut chewing
.
Betel nut, a stimulant from the areca palm tree, is used as a disinfectant and as an as-yet-unproven treatment for problems such as schizophrenia and glaucoma
.
Chewing betel nut is a common cultural practice in South, Southeast and Asia Pacific
.
It is often chewed with products such as tobacco and has been linked to cancer and a range of other medical problems, including slowed heart rate and stomach ulcers
.

Carcinogens primarily damage the lining of the head and neck area, causing one or more mutations that lead to cancer
.

Journal Reference :

1. Hoi-Lam Ngan, Chun-Ho Law, Yannie Chung Yan Choi, Jenny Yu-Sum Chan, Vivian Wai Yan Lui.
   Precision drugging of the MAPK pathway in head and neck cancer .
   npj Genomic Medicine , 2022;7(1) DOI: 10.
   1038/s41525-022-00293-1