Targeting TRK family proteins in cancer.
The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date. Although the NTRK gene fusions are infrequent in most cancer types, certain rare tumor types are predominately driven by these events. Conversely, in more common histologies, such as lung and colorectal cancers, prevalence of the NTRK fusions is well below 5%. Selective inhibition of TRK signaling may therefore be beneficial among patients whose tumors vary in histologies, but share underlying oncogenic NTRK gene alterations. Currently, several TRK-targeting compounds are in clinical development. The ongoing Phase 2 trials with entrectinib and LOXO-101, two of the leading TRK inhibitors, are designed as 'basket trials', inclusive of patients whose tumors harbor NTRK gene fusions, independent of histology. Additional Phase 1 studies of other TRK inhibitors, including MGCD516, PLX7486, DS-6051b, and TSR-011, are underway. Interim data examining NTRK-rearranged tumors treated with entrectinib or LOXO-101 demonstrate encouraging activity, with patients achieving rapid and durable responses. Consequently, both drugs have achieved orphan designation from regulatory agencies, and efforts are underway to further expedite their development.
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Yekaterina B
YB
Khotskaya
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Vijaykumar R
VR
Holla
Department of Medicine, Massachusetts General Hospital, Boston, MA, United States.
Anna F
AF
Farago
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Kenna R
KR
Mills Shaw
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Departments of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Funda
F
Meric-Bernstam
Departments of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address: dshong@mdanderson.org.
David S
DS
Hong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; C000607349:entrectinib; C000609083:larotrectinib
Cancer; Central nervous system; Gene fusions; NTRK1; NTRK2; NTRK3