I.18-1 NTRK Fusion Proteins

Abstract

We have a new approach to cancer therapy “the Agnostic Tumor” approach. Molecular mechanisms (DNA mutations, translocations, deletions, fusions, etc.) are now the ones responsible of the origin and behavior of most of the tumors, instead of the location of the tumor as we used to think. We are in the beginning of changing the focus of cancer therapy from a single organ to a molecular marker envision. One of the best examples are the NTRK fusion proteins, NTRK genes encode for the Trk-family proteins: TrkA, TrkB, and TrkC (encoded by NTRK1, NTTRK2, and NTRK3). Normally, the NTRK family plays a role in the development of the nervous system, however, NTRK fusions are also present in solid tumors as fusion proteins responsible for growth of cancer cells, and the presence of these oncogenes is associate with poor survival in lung cancers and other tumor types. It is not surprising that these oncogenes are present in several different tumors (They are actionable in at least 17 tumor types) including adults and children. These genomic alterations are becoming a great example why the tumor agnostic approach might be the new paradigm in fighting cancer. However, there are still many challenges ahead; first for example, the diagnostic of these genetic aberrations: we can do fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse-transcriptase polymerase chain reaction (RT-PCR) and next generation sequencing (NGS) of DNA or RNA (or cfDNA in blood: liquid biopsies). Each of these approaches has strengths and weaknesses, but we also have to play this in the context of workups for other genetic abnormalities and keeping into consideration that tumor tissue specimen is very limited in many instances. Nowadays, for example, we do FISH for ALK and ROS-1 translocations, if we add three more FISH tests for each of the NTRK alterations (and maybe one more for RET fusions) will markedly increase the costs of workup in a lung cancer patient, and the gene fusion partner, that might become relevant, still might not be identified if we don’t have the right probe. RT-PCR is a great technique, but we will need a lot of primers (there are more than 60 NTRK fusions documented) to cover all the NTRK genetic abnormalities. Probably the solution is to develop better IHC? as we are doing for ALK translocations and hopefully get one day as IHC for ROS-1 and the other NTRK oncogenes so we can have a more cost-effective work up. A more practical approach might be to establish NGS in tissue or blood as the standard of care that can detect all these genetic alterations at once at the time of the diagnosis of the patient? Later we can do a more limited work up if we are looking for ALK and now NTRK resistant variants in patients that have failed treatment clinically. Nonetheless, for those who are not fans of NGS and don’t advocate this approach we can say that several NTRK 1-3 introns are not well covered by NGS. Then, we need to do whole genome gene sequencing to find them increasing the costs of the workup. These are some of the questions that remain open while we make all these diagnostic techniques more accurate and more cost effective. Some of these reasons are responsible to consider the treatment for NTRK challenging: how we can treat a patient if we can’t discover the genetic aberration? We are fortunate to have two agents: entrectenib and larotrectenib that have already been FDA approved for NTRK fusions with acceptable toxicities regardless of tumor type, patient age, and fusion type, and more data coming from other agents in development CEP-701, ARRRY-470 DS-6051b, TPX-0005. Probably LOXO 195 is the one that has been more studied for now and it’s able to rescue patients that develop resistance mutations during the treatment with larotrectenib or entrectinib.