Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

2019 ◽  
Vol 19 (23) ◽  
pp. 2128-2142 ◽  
Author(s):  
Hao He ◽  
Chang Xu ◽  
Zhao Cheng ◽  
Xiaoying Qian ◽  
Lei Zheng
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Combination Therapy ◽  
Clinical Benefit ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Egfr Tki ◽  
Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Optimal Adjuvant Therapy in Resected Stage IIIA-N2 Non-Small-Cell Lung Cancer Harboring EGFR Mutations

2020 ◽  
Vol 43 (12) ◽  
pp. 686-693
Author(s):  
Miaomiao Wen ◽  
Lei Wang ◽  
Xuejiao Wang ◽  
Sanhu Yang ◽  
Ying Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Stage Iiia ◽  
Egfr Tki ◽  
Egfr Tkis

<b><i>Background:</i></b> Some non-small-cell lung cancer (NSCLC) patients are unexpectedly diagnosed with stage IIIA-N2 disease at the time of thoracoscopy or thoracotomy. Because of the limited statistical evidence of induction chemotherapy for these patients, it is necessary to develop more profound treatment strategies. <b><i>Methods:</i></b> The demographic and clinical characteristics of patients with stage IIIA-N2 NSCLC harboring epidermal growth factor receptor (EGFR) mutations after radical resection were retrospectively reviewed. The patients were divided into 3 groups based on treatment: EGFR tyrosine kinase inhibitors (EGFR-TKIs, erlotinib or gefitinib), adjuvant chemotherapy (docetaxel plus cisplatin), and combination treatment (chemotherapy plus EGFR-TKIs). The effect of adjuvant therapy on survival rate was assessed using univariate and Cox regression analyses. <b><i>Results:</i></b> Patients receiving EGFR-TKIs alone showed significantly improved disease-free survival (DFS; <i>p</i> = 0.025) when compared to those receiving chemotherapy alone. Compared to chemotherapy alone, the combination of chemotherapy and EGFR-TKIs resulted did not significantly improve DFS (<i>p</i> &#x3c; 0.001) and overall survival (OS <i>p</i> &#x3c; 0.001). The combination of EGFR-TKIs with chemotherapy as adjuvant therapy led to improvements in both DFS (<i>p</i> = 0.116) and OS (<i>p</i> = 0.039) compared to patients receiving a EGFR-TKI monotherapy. Toxicities were mild in the 3 treatment groups. <b><i>Conclusions:</i></b> Our study demonstrated that adjuvant EGFR-TKI treatment significantly increased the DFS of patients with stage IIIA-N2 NSCLC when compared with cisplatin-based chemotherapy. The use of EGFR-TKIs and chemotherapy is recommended in the setting of combined-modality therapy.

scholarly journals Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance

2020 ◽  
Author(s):  
Xu Zhang ◽  
Tapan K. Maity ◽  
Karen E. Ross ◽  
Yue Qi ◽  
Constance M. Cultraro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Egfr Mutations ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Resistant Cells

AbstractLung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative mass spectrometry dataset to uncover alterations in signaling pathways, reveal a proteomic signature of epithelial mesenchymal transition (EMT) and identify kinases and phosphatases with altered expression and phosphorylation in TKI resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition resulting in inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified dactolisib, a PI3K/mTOR inhibitor, which in combination with osimertinib overcomes resistance both in vitro and in vivo.One Sentence SummaryGlobal quantitative proteome and phosphoproteome analyses to examine altered signaling pathways in isogenic 3rd generation EGFR TKI sensitive and resistant cells.

scholarly journals Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Yijia Guo ◽  
Jun Song ◽  
Yanru Wang ◽  
Letian Huang ◽  
Li Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Efficacy ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Gene Alterations

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
First Line ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third - generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as a second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy, and limited information is available regarding genetic diagnostic approaches after EGFR-TKI naïve treatment. This study investigated the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistance to EGFR-TKIs and the advantages of rebiopsy and liquid biopsy for these patients. Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients were determined to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had new lesions, and were administered gefitinib as first-line therapy, patients harboring an EGFR mutation were suspected of harboring the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors , and these biopsies can be repeated numerous times .

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Liquid Biopsies ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR -mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

Small cell lung cancer (SCLC) among patients who are never smokers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7593-7593
Author(s):  
Anna M. Varghese ◽  
Helena Alexandra Yu ◽  
Helen H. Won ◽  
Camelia S. Sima ◽  
Gregory J. Riely ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Egfr Mutation ◽  
De Novo ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Never Smokers ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Generation Sequencing

7593 Background: Although most patients (pts) with SCLC are current or former smokers, SCLC has been reported in pts who are never smokers, most recently in pts with EGFR-mutant lung cancers who develop acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs). We describe clinical, pathologic, and molecular characteristics of never-smoking pts with SCLC at diagnosis and in the AR setting. Methods: We identified cases through systematic review of pts seen at MSKCC from 2005 – 2012. Smoking history was obtained prospectively. SCLC diagnosis was confirmed by expert pathology review. We collected age, sex, stage, treatment, and survival data. EGFR, KRAS, PIK3CA, and ALK testing and next generation sequencing of 279 cancer genes was performed on available samples. Results: 2.2% (23/1040, 95% CI 1.5 to 3.3%) of pts with SCLC seen at MSKCC were never smokers: 61% women, median 64 years, 74% extensive stage, and 22% with brain metastases at diagnosis. 83% (19/23) had de novo SCLC, whereas only 17% had SCLC as AR to EGFR TKI after treatment for EGFR-mutant lung cancers, all of whom had persistent EGFR mutation confirmed at resistance. Median survival from SCLC diagnosis is 23 months (95%CI: 11-26) for all pts and 23 months (95% CI: 8–27) for the 19 pts with de novo SCLC. Pathologic review demonstrated 19 cases of pure SCLC and 4 mixed histology cases with SCLC and other histologies. Treatment history was available for 15/19 pts with de novo SCLC: 53% etoposide-platinum sensitive. ALK rearrangement and KRAS mutations were identified in 0/5 and 0/10, respectively. One pt with de novo mixed SCLC and adenocarcinoma had an EGFR mutation and another pt with de novo pure SCLC had EGFR and PIK3CA mutations. Mutations were identified in p53 and Rb1 with amplification in TERT in 1 sample to date tested with next generation sequencing. Conclusions: 2% of pts with SCLC are never smokers. While transformation to SCLC can occur in the setting of AR to EGFR TKI, de novo SCLC occurs in the majority of our never smokers with this disease. EGFR mutations uniformly exist in SCLC in the AR setting. EGFR mutations were rare, and we found no KRAS mutations or ALK rearrangements. Comprehensive, multiplexed genotyping can aid in providing optimal care and facilitate research in this unique population.

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
First Line ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than first-generation EGFR-TKIs used for first-line treatment, their efficacy for long-term patient survival remains unclear even upon administration of a complete sequence of EGFR-TKI therapy, and limited information is available regrading genetic diagnostic approaches after EGFR-TKI naïve treatment. This study aimed to investigate the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs and the advantages of rebiopsy and liquid biopsy among these patients.Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs except for osimertinib, single plexus COBAS version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients harbored EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, displayed a new lesion, and were administered gefitinib as first-line therapy, patients harboring an EGFR mutation were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at rare sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors, and these biopsies can be repeated numerous times.

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
First Line ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third - generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy, and limited information is available regrading genetic diagnostic approaches after EGFR-TKI naïve treatment. This study investigated the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs and the advantages of rebiopsy and liquid biopsy for these patients. Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients were determined to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, patients harboring an EGFR mutation were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors , and these biopsies can be repeated numerous times .

scholarly journals Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations

2015 ◽  
Vol 112 (32) ◽  
pp. 9990-9995 ◽  
Author(s):  
Zhijie Wang ◽  
Zhirong Shen ◽  
Zhenxiang Li ◽  
Jianchun Duan ◽  
Shuai Fu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell ◽  
Combined Treatment ◽  
Lung Squamous Cell Carcinoma ◽  
Squamous Cell Carcinomas ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Dual Inhibitor ◽  
Egfr Tki ◽  
Egfr Tkis

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.

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