| Abstract: | ![]()
The empirical criteria for defining a clinical subtype of lung cancer are gradually transiting from histopathology to genetic variations in driver genes. Targeting these driver mutations, such as sensitizing epidermal growth factor receptor (EGFR) mutations, has dramatically improved the prognosis of advanced non–small cell lung cancer (NSCLC). However, the clinical benefit of molecularly targeted therapy on NSCLC appears to be different between lung adenocarcinomas and squamous cell carcinomas (SqCCs). We report here that the resistance of lung SqCC harboring EGFR mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was due to the activation of BMP-BMPR-Smad1/5-p70S6K. The combined treatment of these tumor cells with EGFR-TKI, together with inhibitors specific to BMPR or downstream mTOR, effectively reversed the resistance to EGFR-TKI. Moreover, blocking the whole PI3K-AKT-mTOR pathway with the PI3K/mTOR dual inhibitor BEZ235 also showed efficacy in treating this subtype of lung SqCC. This study details the empirical basis for a feasible clinical solution for squamous cell carcinomas with EGFR mutations.Traditionally, the classification of lung cancer has been based primarily on histology and morphology (1, 2). With the identification of mutated driver oncogenes, methods from molecular pathology are gradually transforming the definition of the various types of lung cancers (3). Targeting gene aberrances such as epidermal growth factor receptor (EGFR) mutations (4–8) and anaplastic lymphoma kinase (ALK) fusion (9, 10) has significantly improved the prognosis of advanced non–small cell lung cancer (NSCLC). However, the clinical benefits brought by targeted therapies are mainly limited to nonsquamous NSCLC (11), while chemotherapy remains the major therapeutic choice for squamous cell carcinomas (SqCCs).Recent studies assessing somatic mutations and copy number alteration (CNA) profiles in SqCC performed by the Cancer Genome Atlas project and other investigators have disclosed specific gene mutations, including GRM8, BAI3, ERBB4, RUNX1T1, KEAP1, and FBXW7, and CNAs in 3q26, 24, 27, 32–34, and 8p12.35 in lung SqCC (12, 13). About half of all patients with lung SqCC carry multiple gene aberrances, indicating that complex genomic characterizations are more common in lung SqCC than in adenocarcinoma (ADC). Thus, successful therapeutic strategies that target a single driver gene in lung ADC might not be feasible for lung SqCC patients.Targeting EGFR mutations by EGFR tyrosine kinase inhibitors (TKIs) is one of the successful strategies in treating lung ADC. EGFR-TKIs obtained median progression-free survival (PFS) of 10–13 mo in EGFR-mutated lung ADC, but only ∼3 mo in lung SqCC with EGFR mutations (11, 14). Moreover, whether EGFR mutations exist in lung SqCC still remains controversial. There is a belief that EGFR mutations might not even occur in pure pulmonary SqCC, and that the occasional detection of these mutations in samples diagnosed as SqCC was due to mixed adenosquamous carcinoma and poorly differentiated ADC (15, 16). In current clinical practice, the utilization of EGFR-TKIs and the assessment of EGFR mutations are still routinely performed in lung SqCC, especially in nonsmokers. Therefore, it is critical to identify the subgroups of lung SqCC patients that are suitable for EGFR-TKI treatment. Exploring the mechanism of resistance to EGFR-TKIs in lung SqCC will deepen our understanding of the differences in tumorigenic profiling between lung SqCC and ADC, and should contribute to guiding clinical therapeutic decisions.In the present study, we demonstrated that lung SqCC patients with EGFR mutations indeed represent a subset of NSCLC. We further showed that lung SqCC cell lines were resistant to EGFR-TKIs both in vitro and in vivo. We also investigated the mechanisms of resistance to EGFR-TKI in this subset of patients and provided potential strategies for overcoming TKI resistance in these patients. |
