Hollander Driver Mutations And

Evidence suggests that mTOR contributes to the resistance of EGFR-TKIs in lung cancer cells ( 9, 10 ).

Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yan Zhang Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yaqing Chen Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jianchang Qian Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Find this author on Google Scholar Find this author on PubMed Search for this author on this site Xuesai Zhang Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ker Yu Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.

Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence.

Hollander Driver Mutations And

Experimental Design: Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine in vitro and in vivo efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelialmesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape.

Results: MTI-31 potently inhibited cell proliferation (IC 50 in vivo tumor growth in multiple NSCLC models of EGFRT790M, EML4-ALK, c-Met, or KRAS (MED Conclusions: Our results highlight mTOR as a multifaceted regulator of tumor growth, metastasis, and immune-escape in EGFRALK-mutant and TKI-resistant NSCLC cells.

The newly characterized mechanisms mediated by the rapamycin-resistant mTORC2 warrant clinical investigation of mTORC1mTORC2 inhibitors in patients with lung cancer.

Translational Relevance Despite recent success in tyrosine kinase inhibitor (TKI) therapy, lung cancer patients often develop resistance and can progress on even the newest generation TKI.

The mTOR signaling pathway is vital to the action of various receptor tyrosine kinase (RTK) pathways and contributes to both intrinsic and acquired TKI-resistance.

With the newly developed mTORC1mTORC2 dual inhibitors, it is important to examine their utility in nonsmall cell lung (NSCLC) tumors with prevalent cancer-driver mutations such as EGFRT790M, EML4-ALK, amplified c-MET and KRAS.

Our results implicate mTOR as a multifaceted regulator of NSCLC tumor growth, metastasis, EMT, and immune-escape, which are critical traits directly linked to disease progression and death.

The newly characterized mechanism mediated by the rapamycin-resistant mTORC2 warrants clinical investigation of mTORC1mTORC2 inhibitors for treatment of TKI nonresponders and acquired resistance in EGFRALK-mutant and PI3KmTOR-dysregulated lung cancer patients.

Introduction Despite significant progress in diagnose and clinical management, lung cancer remains the leading cause of cancer-related deaths worldwide ( 1 ).

Common driver mutations in nonsmall cell lung cancer (NSCLC) are more prevalent in lung adenocarcinoma, in which receptor tyrosine kinases (RTK) including EGFR, EML4-ALK, and c-Met are well-known driver mutations.

Approximately 15 of United States and 40 of Asian NSCLC cases harbor mutations in the EGFR kinase domain ( 3 ).

Although majority of such patients initially benefited from treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI) such as gefitinib and erlotinib ( 4 ), there is a significant heterogeneity in the clinical course of patients with EGFR-mutant lung cancers.

Acquisition of EGFR-T790M is the most frequently identified resistance mechanism, and is detected in tumor cells from more than 50 of patients after disease progression ( 5 ).

Despite a new generation of EGFR-TKIs are approved to treat patients with EGFR-T790M, cancer cells can still develop resistance ( 6, 7 ).

Furthermore, greater than 50 of NSCLC cases are diagnosed at an advanced stage with up to 50 of patients developing brain metastases throughout their disease course ( 8 ), which presents another challenge to successful treatment.

The mTOR is a serinethreonine kinase related to the lipid kinases of the PI3K family.

The PI3KAKTmTOR pathway is one of the most important signaling network downstream of the oncogenic RTKs.

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