Second-generation broad-spectrum anti-cancer TRK inhibitors may solve the problem of ententinib or larotinib resistance

PD-1 inhibitors are undoubtedly milestones in the discovery of large-molecule biopharmaceuser drugs in the field of tumors in recent years, while small-molecule broad-spectrum anti-tumor drugs are of greater concern to TRK inhibitors.
Although the first generation of TRK inhibitors was introduced in 2018-2019, many TRK fusion-positive tumor patients were relieved and the disease was brought under control, some patients eventually developed drug resistance, including on-target and non-target resistance.
against this, 2nd generation drugs have entered clinical development of 1NTRK and 2 1st generation drugs NTRK, the neurotrophic factor receptor tyrosine Kinase, consisting of highly ogenetic kinase TRK-A, TRK-B, TRK-C, which belongs to the NTRK gene code.
1982, kinase TRK-A was identified in two colon cancer patients; although TRK was initially identified in tumor transformation, the family was widely distributed in the nervous system and highly associated with neurodevelopment (PS: adverse reactions are also associated); and the TRK family is also coded TRK-A, TRK-B and TRK-C by NTRK1, NTRK2, and NTRK3.
1. The first drug on the market, Larotrectinib, Janne and Doebele, among others, was initially reported to have found larotrectinib, a pan-TRK inhibitor with an IC50 value between 2-20 nM and a good selectivity for other kinases (statistically, more than 100 times more selective for 229 other kinases and more than 1000 times more selective for 80 non-kinase targets).
approved by the FDA in 2018 (trade name: Vitrakvi) for the treatment of adult and child patients with NTRK gene fusion rather than certain types of cancer.
for larotrectinib, three important clinical trials have been conducted: the Adult Phase I Trial, the Pediatric Phase I/II Trial (SCOUT) and the Adult/Adult Icon II Basket Trial (NAVIGATE), all of which have recruited patients with advanced solid tumors.
2nd listed drug, Entrectinib, is a multi-kinase inhibitor, unlike laroteni.
addition to TRKA/B/C, it also suppresses ROS1 and APK.
such as NTRK fusion-positive KM12 cell line, ROS1 fusion CUTO-27 cell line, ALK fusion NB-1 cell line, etc.
Figure 1.5 Entinib partial inhibition statistics for different cancer types in different cell line (Photo:) For enturcinib, four important clinical trials have been conducted: the Adult Phase I Trial (ALKA-372-001, Italy); Phase I trials (STARTRK-1, global); Phase II clinical trials (STARTRK-2); solid tumor patients with NTRK1/2/3, ROS1 or ARK gene fusion in the group, and Phase I/Ib children's trials (STARTRK-NG).
Figure 1.6 Example: Entourini-STARTRK-2 Basket Trial Research Program (Photo:) The two drugs listed above can treat a variety of types of tumors, including four histological forms rich in NTRK gene fusion (pictured) Breast-like secretion cancer, secretive breast cancer, cervical fibroid sarcoma and congenital mesothelioma), as well as several other malignant tumors, including lung, gastrointestinal, breast and thyroid cancer, melanoma and soft tissue sarcoma.
problems with NTRK-1-generation drugs? The main problem, drug resistance! In addition, adverse reactions such as dizziness and co-effect disorders occur occasionally (as discussed above).
drug resistance is arguably the last thing that wants to happen in the course of cancer treatment.
Today's drug treatment, once drug resistance occurs, the drug needs to be replaced immediately, and many times a batch of drugs can not be used, if there is an iteration of drug use is good, if not, then the patient's condition will rapidly deteriorate and can not be controlled.
has now been found that NTRK inhibitors after treatment for a period of time, there will be certain drug resistance (mainly involving NTRK1/NTRK3), its drug resistance mechanism is mainly TRK kinase domain mutations.
these mutations lead to resistance to TRK inhibitors by interfering with inhibitor binding, altering kinase domain composition, or altering ATP binding affinity.
further studies have found that the occurrence of domain mutations is similar to that of APK and ROS1 kinases, which cause amino acids to be replaced in three main regions: solvent front (solvent frontier mutation), gatekeyer resurride (gatekeeper point mutation) and xDFG-motif structure sequences.
solvent frontier point mutations mainly include TRKA-G595R, TRKB-G639R and TRKC-G623R, similar to ARK-G1202R and ROS1-G2032R; Similar TRKA-F589L, TRKB-F633L and TRKC-F617L;
, in terms of off-target resistance, it is also similar to ARK and ROS1 fusion-positive, and the associated KRAS-MET amplification, BRAF-V600E mutation, and KRAS mutation have been found in tumor and plasma samples of TRK fusion-positive cancer patients;
off-target issues, it is recommended to use a combination of TRK and related kinase inhibitors to combat the resistance of 1 generation of drugs! Figure 2.1 Drug resistance and off-target information for 1st generation TRK inhibitors (Image source: s41571-018-0113-0) Non-target resistance is similar to ARK and ROS1 fusion-positive lung cancer, which can develop non-target resistance to tyrosine kinase inhibitor therapy.
its mechanism mainly includes bypass or downstream path signal activation.
there are KRAS mutations, MET amplification, BRAF V600E mutations, and activation of IGF1R in tumor and/or plasma samples in patients with TRK inhibitor resistance, which may be associated with drug resistance.
3, NTRK 2-generation drugs representing the varieties selitrectinib and repotrectinib second-generation TRK inhibitors were developed to address the first generation of drug resistance.
two major drugs currently under development are sellrectinib and repotrectinib.
and selitrectinib are similar in inhibition activity for wild TRK, but for TRK kinase domain mutations, selitrectinib's IC50 is much lower than Laroteni's.
2nd generation drugs sellectinib and repotrectinib are characterized by small molecular weight, large rings, binding to ATP binding pockets, while avoiding space loss due to kinase domain mutations, and enhanced anti-wild TRKA/B/C activity compared to 1nd generation TRK inhibitors.
selitrectinib and repotrectinib are both well-active for RTK kinase region mutations: IC50s are 2.0-2.3 nM and 2.7-4.5 nM, respectively, for solvent frontier mutations; For gate-controlled mutations, IC50s are 2.0-2.3 nM and slt;0.2nM, respectively; For xDFG replacement, the IC50s are 2.0-2.3nM and 9.2nM, respectively.
Selitrectinib also has clinical representative data on selective cytotoxicity for cell line containing TRK fusion proteins: Nature Review describes 31 cases (20 of which were from phase I clinical trials of LOXO-195, and 11 patients from sympathetic drug programs and those patients who had previously been targeted by NTRK) Patients with TRK fusion-positive cancers with a medium duration of 9.5 months (both treated with previous TRK inhibitors (larotrectinib, entrectinib or PLX7486) received the objective remission rate orR of patients with the most susceptible solvent frontier mutations of 45%.
Selitrectinib and retotrectinib are currently conducting Phase I/II clinical trials (NCT03215511 and NCT03093116).
report the results of the latest clinical trial at the 2019 annual meeting of the American Association for Cancer Research (AACR).
as of December 03, 2018, 31 (7 children, 24 adults) tumor patients, including sarcoma, gastrointestinal mesothelioma, pancreatic cancer, breast cancer and 11 other types of tumor patients, were treated with Selitrectinib.
Selitrectinib treated patients with TRK kinase domain mutations with ORR of 45%, and adverse events (TEAE) during treatment were dizziness, loss of appetite, nausea, vomiting, anemia, myalgia, abdominal pain, fatigue, and lymphocyte reduction.
, Repotrectinib has been shown to regain control of tumor disease after the development of kinase-mediated access resistance for the first generation of TRK inhibitors.
A TRK fusion-positive breast resemblant secretion cancer patient who developed drug resistance to entretinib and was partially relieved after treatment with Repotrectinib.
TRK fusion positive bile tube cancer patient, who developed drug resistance to larotinib and was treated with Repotrectinib and remission.
January 20, Selitrectinib (BAY 2731954) was approved for clinical trials in China as a TRK inhibitor under study.
study found that NTRK fusion-positive tumors occur because the NTRK1/2/3 gene fuses with other genes, leading to abnormalities in the encoded TRK protein and activating signaling paths associated with the proliferation of specific cancers.
NTRK gene fusion may occur in tumors originating in different parts of the body, including breast cancer, bile tube cancer, colorectal cancer, neuroendocrine cancer, non-small cell lung cancer (NSCLC), pancreatic cancer, and so on.
this makes NTRK one of the targets for the development of "unlimited cancer" therapies.
is in the phase 1/2 phase of clinical trials worldwide, according to the website clinicaltrials.gov.
4, TRK inhibitors in the global research situation, through the introduction of two listed drugs and two 2 generations of improved drugs, the development of pan-cancer TRK inhibitors can be generally understood.
foreign development is in full swing at the same time, the domestic is actually gradually catching up, and many 2 generations of drugs have been approved clinically, just a little slower progress.
as a pan-cancer treatment drug, both at home and abroad will naturally not miss.
the end of the article, the author further statistics the global development of TRK inhibitors, so that we can better understand the panoramic competitive landscape of the target.
Schedule: TRK Inhibitors Global Research Reference 1. Drug Data 2. Drilon A. TRK inhibitors in TRK fusion-positive cancers. Ann Oncol. 2019; 30(Suppl_8):viii23–viii30. doi:10.1093/annonc/mdz2823. 4. Lancet Oncol 2020.S1470-2045 (19) 30856-35. Network Source: Web Copyright Notice: All text, images and audio-visual materials on this website that indicate "Source: Mets Medicine" or "Source: MedSci Original" are owned by Metz Medicine and are not authorized to be reproduced by any media, website or individual, and are authorized to be reproduced with the words, images and audio and video materials.
all reprinted articles on this website are for the purpose of transmitting more information and clearly indicate the source and author, and media or individuals who do not wish to be reproduced may contact us and we will delete them immediately.
at the same time reproduced content does not represent the position of this site.
leave a message here