Genetic mutations are alterations in an organism’s DNA sequence. These changes can range from small modifications to large rearrangements. While some mutations have no noticeable effect, others significantly impact protein function. The T315I mutation is an example of such a change, altering disease progression and treatment responsiveness.
What is the T315I Mutation?
The T315I mutation is a point mutation, involving a single change within the DNA code where one nucleotide is swapped for another. This change leads to the substitution of Threonine (T) with Isoleucine (I) at position 315 within a particular protein. This amino acid change occurs within the ABL kinase domain of the BCR-ABL fusion protein.
The BCR-ABL fusion protein is an abnormal protein resulting from a chromosomal rearrangement, frequently observed in chronic myeloid leukemia (CML) and some cases of acute lymphoblastic leukemia (ALL). The ABL kinase domain within this fusion protein acts as an enzyme, playing a role in cell growth and division signaling pathways. The alteration at position 315 is in the ATP-binding domain, a location where many targeted cancer drugs are designed to bind and inhibit the protein’s activity.
How T315I Causes Drug Resistance
Tyrosine kinase inhibitors (TKIs), such as imatinib, were developed to treat cancers like chronic myeloid leukemia by specifically blocking the activity of the BCR-ABL protein. These drugs work by fitting into a specific site on the BCR-ABL protein, preventing it from signaling cancer growth. Imatinib improved CML treatment as a first-generation TKI.
The T315I mutation alters this binding site on the ABL kinase domain. The substitution of Threonine with Isoleucine at position 315 makes it impossible for most first- and second-generation TKIs to bind effectively. This alteration prevents the drug from attaching and inhibiting the protein, rendering cancer cells resistant to these therapies. This broad resistance to commonly used TKIs presents a challenge in managing patients with this mutation.
Treatments for T315I Mutation
Overcoming the resistance caused by the T315I mutation has led to the development of specialized therapeutic strategies. Ponatinib, a third-generation TKI, was designed to target the BCR-ABL protein even with the T315I mutation present. It is effective against most kinase domain mutations, including T315I, and is approved for patients who have not responded to two or more prior TKIs.
Another option is asciminib, approved for CML patients with the T315I mutation or those resistant to, or intolerant of, other TKIs. Asciminib works differently from other TKIs, binding to a unique site on the BCR-ABL protein called the myristoyl pocket. This “allosteric” inhibition mechanism locks the protein in an inactive state, making it effective against the T315I mutation. Both ponatinib and asciminib are important options for these challenging cases. Other approaches may include participation in clinical trials for novel agents or allogeneic stem cell transplantation.
Detecting and Managing T315I
Identifying the T315I mutation is an important step in guiding treatment decisions for patients, especially those with chronic myeloid leukemia (CML). The mutation is detected through specialized genetic testing of patient blood samples. Techniques such as molecular sequencing, including Sanger sequencing and next-generation sequencing (NGS), are employed to identify these specific genetic changes.
Testing for the T315I mutation is performed when a CML patient shows signs of resistance or a warning response to initial TKI therapy. Sanger sequencing has been a standard method, but newer, more sensitive methods like digital polymerase chain reaction (dPCR) and NGS can detect low-level mutations that Sanger sequencing might miss. Once confirmed, management involves switching the patient to therapies effective against this mutation, such as ponatinib or asciminib, and closely monitoring their response.