Imagine a heavy roof propped up by slender pillars. Now imagine knocking down one of those pillars. The others buckle under the weight, and soon the whole thing comes crashing down.
NCI Frederick scientists, with collaborators from the National Institutes of Health, industry, and academia, have achieved something similar in laboratory models of head and neck squamous cell carcinoma (HNSCC), a group of mouth, throat, and nasal cavity cancers with life-altering complications.
They’ve confirmed that a protein called leucine zipper-bearing kinase (LZK) is a key target for potentially treating HNSCC, not just because it helps to prop up these tumors but because inhibiting or eliminating it causes other proverbial pillars to collapse.
According to their study, eliminating LZK reduces two major cancer-driving proteins, c-MYC and mutated p53, so sharply that HNSCC tumor growth slows or halts altogether.
The team has also designed rudimentary drugs, proteolysis-targeting chimeras (PROTACs), that can eliminate LZK in HNSCC cells. It’s a preliminary step on a long road toward a new treatment for HNSCC.
“We really tried to come up with new therapeutic targets in these cancers of unmet need,” said John Brognard, Ph.D., the senior author on the study and a senior investigator in NCI’s Laboratory of Cell and Developmental Signaling.
How LZK Props Up HNSCC…
Past studies, including some authored by members of the team, have shown that some cells with higher-than-normal levels of LZK can become cancerous. Still, it was unclear whether the connection was strong enough for LZK to be a worthwhile target for treating HNSCC.
LZK is “an understudied kinase,” said Meghri Katerji, Ph.D., a co-lead author on the study and a staff scientist in the Laboratory of Cell and Developmental Signaling.
To investigate, the team administered an LZK-inhibiting drug in preclinical models of HNSCC. The drug partially killed some tumors and reduced the growth of others, confirming LZK’s importance to HNSCC, but it also revealed that LZK cooperates with c-MYC and mutated p53 to drive these cancers.
c-MYC depends on functioning LZK in order to persist and contribute to HNSCC, the team found. If LZK is inhibited or eliminated, the amount of c-MYC in the cell plummets—as does the cancer cells’ ability to survive.
This discovery was a welcome surprise. c-MYC is known to drive many cancers when overabundant or dysregulated in cells, like in HNSCC, but is so hard to target it’s regarded as practically undruggable.
“There’s been a huge desire to target MYC,” Brognard said. “So when we found out that this kinase [LZK] was regulating MYC expression, we were really excited because when you have a drug that can really decrease MYC expression, you know that’s really valuable.”
LZK’s connection with mutated p53 was equally interesting, Katerji said. Mutated p53 is known as a major driver of tumor formation and is implicated in many cancers.
Unlike c-MYC, mutated p53 interacts with a fringe portion of LZK’s molecular structure to drive HNSCC, the team found. LZK doesn’t need to be active. The LZK-inhibiting drug, which only blocks the active part of LZK’s structure and not the fringe portions, didn’t affect p53’s cancer-driving ability.
“[That] was probably not my first instinct,” Katerji said of the finding.
…And How to Knock It Down
Motivated by the data, the team designed PROTACs to wipe out LZK. PROTACs are conjoined molecules engineered to find a specific type of protein, attach to it, and signal a cell’s built-in cleanup mechanisms to destroy it.
One of the PROTACs devastated LZK levels in laboratory models of HNSCC tumors, with c-MYC and p53 levels also decreasing. Treated HNSCCs grew slower than untreated ones, starved of the proteins they needed to thrive.
“By targeting LZK, we’re able to target an undruggable target,” Katerji said, referring to c-MYC.
The Long Road Ahead
Although the findings warrant some optimism, PROTACs against LZK aren’t ready for use in humans with HNSCC.
Laboratory models don’t perfectly reflect human biology, and other studies have shown the difficulty of engineering PROTACs to enter the right cells and hit targets in humans.
The team’s PROTACs also had to be administered at high doses to slow tumor growth in the models, and doses capable of halting growth entirely were harmful to healthy cells. Clinical trials will be required to determine whether the approach is safe and effective in people.
Even so, the team hopes the approach may eventually help people battling a devastating form of cancer. Until then, their revelations about c-MYC and p53 can foster other developments.
“Seeing the translational work from the [lab] bench and potentially getting that to clinical trials would be a dream come true for me,” Katerji said.
Samuel Lopez leads the editorial team in Scientific Publications, Graphics & Media (SPGM). He writes for newsletters; informally serves as an institutional historian; and edits scientific manuscripts, corporate documents, and sundry other written media. SPGM is the creative services department and hub for editing, illustration, graphic design, formatting, multimedia, and training in these areas.