Cancer Cell provides new evidence: deleting a gene turns normal cells into cancer cells

A team led by researchers at the Permatt Cancer Center at NYU Langone Health Center has identified a gene that drives the development of the second most common type of lung cancer, providing deeper insights
into how to treat the disease.

There is currently no approved, targeted first-line treatment
for lung squamous cell carcinoma (LUSC).
LUSC is a type of cancer that forms in the cell layer within organs and causes 20% to 30% of lung cancer deaths
.
But a new study published in the Jan.
9 issue of Cancer Cell has found that deleting a gene called KMT2D causes normal (basal) lung cells grown in complex organoid cultures to be transformed into LUSC cells
.

According to the study authors, KMT2D regulates the activity of genes that enable the construction of protein tyrosine phosphatase, an enzyme that inhibits cell growth encouragement signals
sent through another group of enzymes called receptor tyrosine kinases (RTKs).
Two RTKs, called EGFR and ERBB2, are known to be involved in abnormal activation of the RTK-RAS signaling pathway, in which a molecular switch is "stuck in open mode," causing cells to multiply
as part of cancer.

"Our study identifies KMT2D as a key factor in the development of lung squamous cell carcinoma and provides important clues on how to target LUSCs with KMT2D deficiency," said
co-corresponding author Kwok Kin-Wong, M.
D.
, director of the Division of Hematology and Medical Oncology at NYU Langone Health.
"The same genetic changes that cause this gene to cause cancer also produce tumors
that are very sensitive to existing drugs that target the relevant pathway.
"

Suggested new approach

The new study confirms previous evidence that the KMT2D gene encodes a protein (histone methyltransferase) that determines the extent to which the tyrosine phosphatase gene can be accessed by cellular mechanisms that attempt to
read them.

Given that the new study has a better understanding of the LUSC mechanism, the team chose to test a combination of two drugs — the SHP2 inhibitor SHP099 and the ubiquitinib inhibitor afatinib
— in study mice.
ERBB becomes more active due to KMT2D signaling defects, while the enzyme SHP opens the RTK-KAS pathway, just like EGFR and ERBB2, which become more active
due to the lack of KMT2D.
The team reasoned that experimental drugs designed to inhibit SHP may also counteract the effects
of KMT2D defects when used with ERBB inhibitors.

In fact, they found that the combination slowed lung tumor growth in modified LUSC mice lacking KMT2D, as well as in mice from human LUSC tumors with KMT2D mutations
.

"Multiple SHP2 inhibitors are currently being tested in clinical trials, and afatinib is already available," said co-corresponding author Hua Zhang, Ph.
D.
, a former lecturer in the Department of Medicine at NYU Langone School of Health and now an assistant professor
in the Division of Hematology and Oncology in the Department of Medicine at the University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center.
"Our findings demonstrate the correct clinical trial design to test these therapies in LUSC patients with KMT2D deficiency
.
"