Gilteritinib overcomes Lorlatinib resistance in ALK-rearranged cancer
by Mizuta et al. (Japan)
A common problem we face is that cancer becomes resistant to our TKIs (Crizotinib, Brigatinib, Alectinib, Ceritinib, and Lorlatinib) over time. There are two known mechanisms so far for resistance. One is for the cancer cells to activate an alternative bypass pathway such as EGFR, cMET, KRAS, or AXL to allow cancers to continue to grow. Alternatively, a secondary mutation in the aberrant ALK fusion can sidestep the efficient TKIs with secondary compound mutations (C1156Y + L1198F or I1171N +L1256F or I1171N + L1198F or I1171N +L1196M or G1202R +L1196M). In the image below, the letters in front of the numbers indicate the amino acid. The numbers in the middle indicate the location on the ALK gene. The second number is the CHANGED amino acid. For example, C1156Y means the Cysteine at #1156 is changed to Tyrosine. These changes can affect how well a TKI can gain access to the aberrant ALK to effectively turn it off. These are called solvent-front and gatekeeper mutations. To find out which amino acid is coded by which letter, look at the Figure to the left.
As shown by Turning Point Therapeutics (a pharmaceutical company), their illustrations below show these combination changes well. The changes are indicated as the little light blue wiggle. If the cells developed the change, it is then hard for the medicine (blue-ish green tadpole shape) to fit correctly into the blue aberrant ALK.
Image from Turning Point Therapeutics, a pharmaceutical company
A group of researchers in Japan decided to tackle this problem of resistance by scanning what medicine can affectively treat tumors that has these compound mutations. Out of over 90 inhibitors that they scanned, they found a medicine called Gilteritinib that can overcome these compound mutations.
Using known resistant cells in a petri dish, they found that Gilteritinib can kill these cells where Lorlatinib and other ALK TKIs have failed. This result was verified in a mouse model system.
In addition, the scientists have found Gilteritinib can stop the ALK aberrant signaling by detecting the lack of autophosphorylation (adding a phosphate) of the ALK kinase. The phosphorylation state indicates the activity level of the kinase. If there’s a phosphate added, the kinase is active; and vice versa.
The group used a computer simulation to predict the binding capability of Gilteritinib, a medicine sold under the brand name Xospata. It is currently FDA approved for inhibiting FLT3, another tyrosine kinase, in acute myeloid leukemia (AML). In European Commission and Japan, this medicine is already approved for use in AML patients. Australia approved it in March 2020 for AML patients.
The authors wanted to find out how Gilteritinib can achieve this wonderful ability. They hypothesized that Gilteritinib can inhibit AXL, a cancer-causing pathway; this hypothesis is supported by a more recent finding by another group, Taniguich et al. This AXL pathway has been linked to EGFR resistant lung cancer and AXL seems to be upstream of several known cancer pathways such as JAK/STAT and PI3K/AKT/mTOR. One of the main purposes of AXL is to modulate the extracellular matrix and mediate cell aggregation.
The authors checked if Gilteritinib can affect KRAS signaling. They did find that there is some downregulation of the KRAS signaling however it is only partial. The authors can inhibit the KRAS signaling by using Gilteritinib with an KRAS G12C specific inhibitor called AMG510. The combination of the two drugs together inhibited KRAS pathway well.
Additionally, they checked for inhibition of EGFR pathway. Similar to the KRAS pathway, the authors found the need to combine Gilteritinib with an EGFR specific TKI like afatinib before the cell growth is inhibited.
Preliminary results also indicates that Gilteritinib may affect ROS1 and/or NTRK1 rearranged tumors as well.
https://www.nature.com/articles/s41467-021-21396-w
https://en.wikipedia.org/wiki/Gilteritinib
https://en.wikipedia.org/wiki/AXL_receptor_tyrosine_kinase
https://biologydictionary.net/amino-acids/
https://tptherapeutics.com/our-science/
Author: Alice Chou