Drusbosky et al. J Hematol Oncol (2021) 14:129 https://doi.org/10.1186/s13045-021-01138-7 REVIEW Open Access Therapeutic strategies in METex14 skipping mutated non-small cell lung cancer Leylah M. Drusbosky2, Richa Dawar3, Estelamari Rodriguez3 and Chukwuemeka V. Ikpeazu1,3* Abstract METex14 skipping mutations occur in about 3–4% of lung adenocarcinoma patients and 1–2% of patients with other lung cancer histology. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are established oncogenic drivers of NSCLC. A mutation that results in loss of exon 14 in the MET gene leads to dysregulation and inappropriate signaling that is associated with increased responsiveness to MET TKIs. Results from GEOMETRY mono-1 and VISION Phase I/II clinical trials demonstrated signifcant clinical activity in patients treated with the MET Exon 14 skipping mutation inhibitors capmatinib and tepotinib with tolerable toxicity profle. In the GEOMETRY mono-1 trial, capmatinib was especially active in treatment-naïve patients supporting the upfront testing of this oncogenic driver. Tepotinib demonstrated superior activity in the pretreated patients in the VISION trial. Savolitinib is another MET TKI that has shown efcacy in the frst- and second-line settings, including patients with aggressive pulmonary sarcoma- toid carcinoma. These studies have demonstrated that these TKIs can cross the blood brain barrier and demonstrated some activity toward CNS metastases. MET Exon 14 skipping mutation is detected by NGS-based testing of liquid or tissue biopsies, with preference for RNA-based NGS. The activity of capmatinib and tepotinib is limited by the devel- opment of acquired resistance. Current research is focused on strategies to overcome resistance and improve the efectiveness of these agents. Our aim is to review the current status of MET Exon 14 skipping mutation as it pertains NSCLC. Keywords: NSCLC, MET Exon 14 skipping (METex14), Tyrosine kinase inhibitor, Metastasis Introduction ERBB2, rearrangements in ALK, ROS1, RET, and NTRK, Comprehensive genomic testing is now standard of care MET amplifcation or exon 14 skipping mutations, PD-L1 in the management of advanced/metastatic non-small expression, and tumor mutational burden. Terapies tar- cell lung cancer (NSCLC). Genomic testing identifes geting these biomarkers have demonstrated greater ef- common or uncommon actionable genomic alterations cacy when compared to chemotherapy [4–6]. that impact therapeutic decision making [1, 2]. Te Te mesenchymal–epithelial transition (MET) is a National Comprehensive Cancer Network (NCCN) tyrosine kinase receptor that is mostly expressed in guidelines recommend testing for certain molecular and epithelial cells, whose natural ligand is the hepatocyte immune biomarkers in patients with advanced/meta- growth factor (HGF). MET signaling has been demon- static NSCLC to assess eligibility for targeted therapy strated to involve cell proliferation, migration, invasion, or immunotherapy [3]. Predictive biomarkers include and survival [7]. Genomic alterations in MET include activating mutations in EGFR, BRAF, KRASG12C, and MET exon 14 skipping mutations (METex14) or acti- vating mutations, MET gene amplifcation, and MET *Correspondence: [email protected] protein overexpression. However, the presence of MET 1 University of Miami Sylvester Comprehensive Cancer Center, 8100 SW exon 14 skipping mutations is currently, the best-defned 10th Street, Ste 3310F, Plantation, FL 33324, USA predictive biomarker for the use of MET tyrosine kinase Full list of author information is available at the end of the article © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Drusbosky et al. J Hematol Oncol (2021) 14:129 Page 2 of 10 inhibitors (TKIs). MET exon 14 skipping mutations the src homology 2 domain-containing 5’ inositol phos- occur in about 3–4% of patients with adenocarcinomas phatase (SHP2); and the signal transducer and activator and in about 1–2% of patients with other NSCLC his- of transcription STAT3. Unique to c-MET is its assem- tology (squamous and sarcomatoid lung cancer) [8]. It blage with GRB2-associated binding protein 1 (GAB1) appears that this alteration is more frequent in older which is a multi-adaptor protein that creates binding women who are non-smokers [9]. MET gene amplifca- sites for additional downstream receptors upon phos- tion which can be due to the increased gene copy number phorylation. GAB1 can either bind directly to c-MET or or due to the transcriptional regulation has been detected indirectly via GRB2. Downstream responses of c-MET in many diferent types of tumors. It has particularly been activation include AKT-mediated cell survival, STAT3- associated with a mechanism of resistance to EGFR TKIs mediated cell proliferation, and ERK/MAPK-mediated with low response to MET inhibitors [10]. While coex- cellular migration and invasion [13] (Fig. 1). istence of METex14 with other oncogenic drivers is not Negative regulation of c-MET is necessary for main- common, METex14 and MET amplifcation have been taining a tightly controlled activity. Te Y1003 site is reported together [11]. Both METex14 and MET ampli- a negative regulatory site which is located in the jux- fcations are associated with poor prognosis in patients tamembrane domain that acts by recruiting c-CBL. with NSCLC. Regulation of c-MET also occurs via its binding to vari- MET TKIs are divided into types I (subtype Ia and ous protein tyrosine phosphatases (PTPs). Tese PTPs Ib), II, and III. Type Ia inhibitors (e.g., crizotinib) block remove phosphoryl groups on the tyrosines within the ATP binding to prevent phosphorylation/activation of c-MET kinase or docking sites. Lastly, binding of PLCg the receptor; type Ib inhibitors (e.g., capmatinib, tepo- to c-MET activates protein kinase C (PKC) which can tinib, savolitinib, AMG 337) are more specifc for MET negatively regulate receptor phosphorylation and activ- than type Ia inhibitors. Type II inhibitors (e.g., cabozan- ity. Aside from PKC activation, increases in intracellular tinib, glesatinib, merestinib) competitively bind a hydro- calcium levels may also result in the negative regulation phobic pocket adjacent to the ATP-binding site. Type of c-MET [14]. III (e.g., tivantinib) inhibitors bind allosteric sites rather MET exon 14 skipping mutations result in base substi- than the ATP-binding site [12]. Generally speaking, the tutions or indels (likely deletions) that disrupt the branch outcomes of NSCLC patients with MET exon 14 skipping point of intron 13, the 3′ splice site of intron 13, or the treated with currently available therapies are poor. Te 5′ splice site of intron 14 [15]. Te region of the protein results from the GEOMETRY mono-1 and VISION tri- encoded by exon 14 includes Y1003, which is the binding als, respectively, led to the recent regulatory approval of site of ubiquitin ligase CBL. MET degradation is medi- capmatinib, and tepotinib was granted priority review for ated by ubiquiting ligase CBL. Tese somatic mutations the treatment of this population of NSCLC patient with afect the RNA-dependent splice sites of exon 14 of the advanced disease. Tese results validate MET exon 14 gene and activate MET activity via reduction of MET skipping mutations as important oncogenic targets and degradation which increases MET stability and activ- underscore the need for routine testing by liquid or tissue ity. Tere are various molecular variations of MET exon biopsies. 14 skipping alterations, as they exhibit highly diverse sequence compositions, making these mutations difcult Molecular biology of METex14 skip mutation to detect. Te loss of METex14 results in increased MET c-MET is known to be expressed in epithelial cells of stability, prolonged signaling upon HGF stimulation, and various organs including pancreas, liver, kidney, pros- increased oncogenic potential. MET exon 14 skipping tate, muscle, and bone marrow. When HGF binds to mutations may be may due to genomic deletions ranging c-MET, the receptor undergoes homodimerization with in size from a 2-base pair deletion to 193-base pair dele- subsequent phosphorylation of two tyrosine residues tion afecting the splice acceptor or splice donor site, or Y1234 and Y1235, located in the catalytic loop of the point mutations involving Y1003 [12]. TK domain. Subsequently, Y1349 and Y1356 located within the carboxy-terminal tail also become phospho- Detection of METex14 skipping alterations in tissue rylated, forming a tandem