Medically reviewed by Dr. Brian Koffman
The Bottom Line:
Bruton tyrosine kinase (BTK) degraders are a new therapeutic area that might be able to overcome mutations that cause resistance to BTK inhibitors.
Who Performed the Research and Where Was it Presented:
Dr. Omar Abdel-Wahab from Memorial Sloan Kettering Cancer Center and colleagues presented the results at the American Society for Hematology Annual Meeting 2022.
Background:
The B-cell receptor pathway is critical for the survival of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) cells. Drugs that block the B-cell receptor and its signaling pathway kill CLL / SLL cells and can provide long remissions for patients. The covalent (irreversible) Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, acalabrutinib, and zanubrutinib, are examples of drugs that block the B-cell receptor pathway. However, patients can develop a C481 mutation in BTK that prevents BTKi from binding and causes drug resistance. This has resulted in a need for other drugs that can overcome this resistance. Noncovalent (reversible) BTKi, such as pirtobrutinib and nemtabrutinib, bind to BTK in a different way that appears to allow them to overcome the C481 mutation that prevents covalent BTKi from working. However, they are susceptible to other BTK resistance mutations.
In this interview, Dr. Brian Koffman interviewed Dr. Omar Abdel-Wahab, Chair of the Molecular Pharmacology Program at Memorial Sloan Kettering Cancer Center in New York, NY. They discussed BTKi resistance mutations and some unique ways of potentially overcoming those mutations.
Methods and Participants:
This research was done in the laboratory with cells in a dish.
Results:
- Current BTKi blocks the enzymatic activity of BTK. So the protein is still there, but it can’t function.
- When patients became resistant to covalent BTKi, the BTK enzyme was no longer functioning, but surprisingly it had new B-cell receptor signaling activity that allowed CLL cells to survive. This is thought to be through a “scaffolding” mechanism.
- This shows that even though the BTKi is blocking the enzymatic activity of BTK, the protein is still finding new ways to signal so the CLL cells can survive.
- Targeted protein degradation is a relatively new concept, where scientists are trying to eliminate cancer-causing proteins, in this case, BTK, from the body.
- Researchers are now looking into drugs that completely degrade or erase unmutated and mutated BTK.
- These BTK degraders are currently in phase 1 clinical trials to determine their safety.
- We previously covered initial results from a first-in-human phase 1 clinical trial of the BTK degrader NX-2127 here.
- If you’re interested in participating in a clinical trial of a BTK degrader, the following studies are available:
Conclusions:
CLL / SLL cells find ways to get around both covalent and noncovalent BTKi by developing resistance mutations. Bruton tyrosine kinase (BTK) degraders are a new therapeutic area that might be able to overcome mutations that cause resistance to BTK inhibitors.
Links and Resources:
Watch the interview on the abstract here:
The full ASH abstract is: Kinase Dead BTK Mutations Confer Resistance to Covalent and Noncovalent BTK Inhibitors but Are Susceptible to Clinical Stage BTK Degraders.
Take care of yourself first.
Ann Liu, PhD
