Predictive Biomarkers of Response to Src Inhibitors in Lung Cancer. Getting to YES1

During the last 15 years, predictive molecular pathology and precision medicine have revolutionized the clinical management of non–small cell lung cancer (NSCLC). Mutations that are essential for malignant growth (i.e., driver mutations) are commonly associated with oncogene addiction, or dependence of some cancers on one gene for the maintenance of the malignant phenotype. The discovery of driver mutations in NSCLC has led to the incorporation of tumor molecular genotyping into therapeutic decision making and the development of new therapeutic options, such as TKIs (tyrosine kinase inhibitors) for oncogene-addicted patients with NSCLC (e.g., EGFR, ALK, and ROS1). Unfortunately, despite the identification of new driver mutations and significant advances in targeted therapies, the 5-year survival rate for lung cancer remains less than 20% (1). Thus, additional strategies to treat lung cancer are urgently needed.

Src family tyrosine kinases regulate multiple genetic and signaling pathways involved in the proliferation, survival, angiogenesis, invasion, and migration of cancer cells (2). Increased Src expression was reported in 60–80% of adenocarcinomas and in 50% of squamous cell carcinomas isolated from patients with NSCLC (3). Src family TKIs have been investigated in clinical trials, but phase 2 trials testing single-agent Src inhibitors in previously treated patients with advanced NSCLC were disappointing (4–6), with one trial showing no activity (6). However, other trials demonstrated marked activity in one patient and prolonged stable disease in several others (4, 5), suggesting there may exist a subset of Src inhibitor–responsive patients with NSCLC that remains molecularly undefined.

In this issue of the Journal, Garmendia and colleagues (pp. 888–899) (7) bring new insight into whether Src family tyrosine kinases may serve as potential therapeutic targets by investigating YES1 genetic alteration in NSCLC. YES1 is a member of the Src family tyrosine kinases and has been shown to play a role in nuclear translocation of EGFR (8) and acquired resistance to EGFR inhibitors in EGFR-mutant lung cancers (9). In this study, Garmendia and colleagues showed using immunohistochemistry that YES1 protein expression is higher in lung cancer cells than normal lung bronchiolar cells. In two cohorts of patients with NSCLC who underwent surgical resection, high YES1 protein expression was an independent predictor of shorter overall survival. Analysis of patients with NSCLC in The Cancer Genome Atlas identified YES1 gene amplification in 15% of lung adenocarcinoma and 25% of patients with lung squamous cell carcinoma. Thus, YES1 is amplified in a significant subset of NSCLC, and its expression correlates with shorter overall survival in patients with NSCLC.

The authors demonstrated that stable YES1 overexpression in human NSCLC cell lines induced proliferation in vitro and increased tumor growth and metastasis in subcutaneous mouse models in vivo. Conversely, genetic depletion of YES1 using siRNAs or CRISPR/Cas9 in human NSCLC cell lines reduced proliferation, survival, and invasion in vitro and tumor growth and lung metastatic growth in vivo. Treatment with the Src inhibitor dasatinib inhibited lung cancer proliferation, invasion, and migration in vitro and growth of subcutaneous tumors in vivo. Garmendia and colleagues also showed that in vivo, dasatinib treatment decreased tumor volume in high YES1-expressing NSCLC cell lines and patient-derived xenograft tumors, whereas low YES1-expressing NSCLC cell lines and patient-derived xenograft tumors were more resistant to dasatinib treatment. These data suggest that YES1 copy number and YES1 protein expression may predict which patients with NSCLC will respond to Src inhibitors.

On the basis of these data, the authors conclude that YES1 should be evaluated clinically as a stratification biomarker for those who may benefit from current or novel Src family TKIs. However, this conclusion must be tempered by experiences targeting kinases with copy number gain and/or overexpression from previous lung cancer trials. Although there has been great success in targeting lung cancer driver mutations in the form of somatic mutations and translocations, disease response to inhibition of potential drivers based on gene amplification and/or protein expression has been less robust. For example, FGFR1 (fibroblast growth factor receptor 1) and MET (hepatocyte growth factor receptor) are two potential therapeutic targets in NSCLC with preclinical studies identifying gene copy number gains and/or overexpression in tissue samples (10–12). However, the initial clinical trials testing inhibition of these targets in patients with NSCLC has been underwhelming.

Ongoing efforts in targeting MET activation have focused on clarifying the exact biomarker needed to determine clinical response (12, 13). Refining the biomarker to focus on MET exon 14 deletion, which leads to MET protein overexpression and activation, as well as clearly defining locus specific amplification and the amount of MET amplification needed to predict response, have led to improved clinical outcomes (13). FGFR1 amplification was also thought to be a potential driving oncogene in squamous cell carcinoma of the lung in preclinical models. However, initial trials of TKIs for FGFR1, based on FGFR1 copy number gain, demonstrated only modest activity in single-group phase 2 trials (14–16). This has led to ongoing studies of additional biomarkers needed to predict clinically meaningful FGFR1 inhibition in patients with NSCLC.

Clearly, additional targeted therapies for NSCLC is an area of great need, particularly in squamous cell carcinoma, for which there has yet to be a successful demonstration of targeted therapy. Members of the Src family tyrosine kinases, including YES1, represent an exciting area of potential future targets for personalized treatment of patients with NSCLC. A full understanding of this proto-oncogene and how it can be measured in a clinically meaningful way is essential to move inhibition of YES1 and other Src family tyrosine kinases forward as effective lung cancer treatment. The work of Garmendia and colleagues has established YES1 as a target worth pursuing.