Boehringer, Puma repurposing lung cancer drugs in leukemia

EGFR inhibitors, which block a key signaling pathway in solid tumor growth, are best known as treatments for lung cancer. But a new study led by scientists at the University of Liverpool found that some of them could potentially be used against blood cancers, too.

Their effectiveness in blood cancers is not related to the EGFR mechanism, they believe. Instead, it’s the drugs’ off-target effect on a pseudo-kinase known as TRIB2, which is part of a protein family called Tribbles, named after the small, fluffy fictional species from Star Trek. Just like tribbles in the sci-fi universe move slowly but reproduce rapidly, Tribbles in the real biology world are unable to catalyze chemical reactions. That’s why they are sometimes referred to as “zombie” enzymes. But they do promote cell survival and drug resistance in both solid tumors and blood cancers.

In their study, the researchers found that the unique disposition of cysteine residues in TRIB2 makes it vulnerable to destabilization by several seemingly unrelated FDA-approved EGFR inhibitors, including Boehringer Ingelheim’s Gilotrif, Puma Biotechnology’s Nerlynx and AstraZeneca’s Tagrisso. The researchers described their findings in the journal Science Signaling.

Using a human acute myeloid leukemia cell line, the team showed that Gilotrif and Nerlynx could successfully kill blood cancer cells in vitro. The drugs, which are actually dual EGFR/HER inhibitors, are 10- to 20-fold more effective at cell killing compared to two EGFR-specific inhibitors, Astellas and Genentech’s Tarceva and AstraZeneca’s Iressa.

EGFR mutation is associated with about 30% of non-small cell lung cancers. Gilotrif was first approved by the FDA in 2013, having been shown to delay tumor growth 4.2 months longer than what was seen in patients receiving chemotherapy. The drug has yielded share to new generations of EGFR inhibitors such as Tagrisso.

Repurposing could give drugs like Gilotrif a second life, the authors of the new study believe. “A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins. Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer,” said Patrick Eyers, the study’s senior author, in a statement.

Interestingly, not all dual EGFR/HER2 blockers examined by the team worked in the same way or showed the same level of potency. Novartis’ Tykerb and Takeda’s investigational TAK-285 actually stabilized TRIB2 in vitro rather than disrupting it.

The preliminary data opens the possibility of using EGFR inhibitors as TRIB2-degrading agents. For future studies, the researchers plan to better quantify the effects of these drugs on the TRIB2 protein by studying clinical samples from patients “as part of broader proteomics approaches to establish all the intracellular targets of such compounds,” they wrote in the study.

https://www.fiercebiotech.com/research/star-trek-protein-helps-repurpose-egfr-lung-cancer-drug-for-leukemia