Jessai Flores.

Two new Yale-led studies published in Nature on Nov. 24 have revealed further details regarding the  anaplastic lymphoma kinase molecule, or ALK, and its role in the formation of cancer. 

After years of research attempting to uncover more about ALK, these two studies have made progress in determining its structure status as a receptor protein. Daryl Klein, assistant professor of pharmacology at the Yale School of Medicine, is a senior author of one of the studies, meanwhile, Joseph Schlessinger, professor of pharmacology and co-director of the Cancer Biology Institute, is the senior author of the other. 

“[ALK] is one of the receptor tyrosine kinases whose aberrant activation causes carcinogenesis,” wrote Tongqing Li, postdoctoral associate in Klein’s Lab. “Physiologically, ligand binding [the specific signal] triggers ALK activation. But how this happens is unknown. Our structures show how ligand binding drives two receptors together.”

ALK, like other receptors, functions to receive signals from other parts of the body to synthesize new proteins or complete other actions. The activation of the receptor depends on the attachment of the ligand and dimerization, the process by which receptors are internalized in cells and complete the necessitated action. 

ALK receptors are generally located in the brain and the central nervous system, and they are activated by binding ligands. Though it is still unknown what ligands bind to it specifically, the internalization of the receptor into the cell, or dimerization, has been implicated in the growth and development of cancer; furthermore, as a tyrosine kinase, ALK serves as a key on and off switch for cellular functions. 

“The receptor tyrosine kinase ALK was originally discovered as an oncogenic fusion protein,” Schlessinger wrote in an email to the News. “At least 20 distinct partners of oncogenic ALK-fusion proteins generated by chromosomal translocations were discovered as key drivers of a variety of cancers including large B-cell lymphomas and inflammatory myofibroblastic tumors. Oncogenic ALK mutants were also identified in pediatric neuroblastoma.” 

The dimerization of the ALK receptor has been linked with the development of these cancers, and it can occur through mutations in nervous tissue cells. Furthermore, chromosomal translocation, or the interchange of chromosome parts, can also stimulate ALK tyrosine kinase activity and lead to these cancers. 

The discoveries regarding the structure of ALK receptors can explain the mechanism for how receptor tyrosine kinases are activated. By understanding the mechanisms, pharmaceutical companies can adopt new ALK inhibitor drugs to prevent the activation of these receptors and provide treatment for some cancers. These treatments could be applied to diseases like neuroblastoma, one of the more common pediatric cancers which accounts for around 12 percent of childhood cancer mortality, according to Klein. 

“The protein we observed through our experiments revealed a surprising architecture,”  Klein wrote in an email to the News. “It can be broken down into 3 regions. A handle, a rigid pole-like extension and a sensor. The rigid pole region we named the ‘pole’ because of its rod-like appearance, and pole is short for Polyglycine Extension. The sensor region or PXL (Polyglycine eXtension Loops), is what ‘captures’ a second ALK protein. And when 2 ALKs come together in this way it activates the receptor to signal.”

Because of the discovery of this structure and mechanism of the receptor, the inhibitors for ALK are intended to target and bind to ALK’s sensor region in order to prevent its activation and the growth signals for the cancer. However, given that cancers are constantly evolving and mutating, the inhibition mechanism itself cannot be a permanent treatment. 

Research is being conducted with the hopes of finding a combination of the inhibition mechanism and antibodies that would be able to effectively disable ALK’s activation complex. This would work around the deficiencies of the chemical inhibitor treatment and apply the structural findings to a potent treatment utilizing the strength of antibodies. 

“In some ways, cancer can be viewed as having the same challenges as SARS COV-2,” Klein wrote to the News. “Just as we use antibodies and small molecules to overcome Covid, now we have a new blueprint for ALK to overcome neuroblastoma. We can use the same analogy to understand oncogenic mutations in ALK. This is an area of ongoing research for us. Any mutation in this uniquely folded glycine rich pole region will certainly cause a misfolding or bending that’s not able to turn off. So we are trying to find ways to ‘fix’ it, in instances where such mutations are associated with cancer.” 

The lab work was conducted at the Yale School of Medicine in Klein and Schlessinger’s labs, along with contributions from the Department of Structural Biology at St. Jude Children’s Research Hospital. 

Manas Sharma | manas.sharma@yale.edu