Highlights in lung cancer

Brambilla, Christian; Spiro, Stephen

doi:10.1183/09031936.01.00238801

Cited by 4 publications

(3 citation statements)

References 16 publications

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“…EGFR and its family members are the major groups of receptor tyrosine kinases that are aberrantly activated in many NSCLCs [ 15 ]. EGFR is over-expressed in more than 60% of NSCLC cases [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer

Lin

Zhong

et al. 2014

Mol Cancer

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BackgroundGPRC5A is a retinoic acid inducible gene that is preferentially expressed in lung tissue. Gprc5a– knockout mice develop spontaneous lung cancer, indicating Gprc5a is a lung tumor suppressor gene. GPRC5A expression is frequently suppressed in majority of non-small cell lung cancers (NSCLCs), however, elevated GPRC5A is still observed in a small portion of NSCLC cell lines and tumors, suggesting that the tumor suppressive function of GPRC5A is inhibited in these tumors by an unknown mechanism.MethodsIn this study, we examined EGF receptor (EGFR)-mediated interaction and tyrosine phosphorylation of GPRC5A by immunoprecipitation (IP)-Westernblot. Tyrosine phosphorylation of GPRC5A by EGFR was systematically identified by site-directed mutagenesis. Cell proliferation, migration, and anchorage-independent growth of NSCLC cell lines stably transfected with wild-type GPRC5A and mutants defective in tyrosine phosphorylation were assayed. Immunohistochemical (IHC) staining analysis with specific antibodies was performed to measure the total and phosphorylated GPRC5A in both normal lung and lung tumor tissues.ResultWe found that EGFR interacted with GPRC5A and phosphorylated it in two conserved double-tyrosine motifs, Y317/Y320 and Y347/ Y350, at the C-terminal tail of GPRC5A. EGF induced phosphorylation of GPRC5A, which disrupted GPRC5A-mediated suppression on anchorage-independent growth of NSCLC cells. On contrary, GPRC5A-4 F, in which the four tyrosine residues have been replaced with phenylalanine, was resistant to EGF-induced phosphorylation and maintained tumor suppressive activities. Importantly, IHC analysis with anti-Y317/Y320-P sites showed that GPRC5A was non-phosphorylated in normal lung tissue whereas it was highly tyrosine-phosphorylated in NSCLC tissues.ConclusionGPRC5A can be inactivated by receptor tyrosine kinase via tyrosine phosphorylation. Thus, targeting EGFR can restore the tumor suppressive functions of GPRC5A in lung cancer.

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Section: Introductionmentioning

confidence: 99%

EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer

Lin

Zhong

et al. 2014

Mol Cancer

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“…The combination of a PI3K inhibitor with an anticancer agent is therefore believed to increase the efficacy of the drug or to decrease drug resistance [33], [34]. In this study, we investigated the anticancer activity of BO-1509 in combination with LY294002 against non–small cell lung cancer (NSCLC), which accounts for approximately 80% of lung cancer cases [35]. More than half of patients with NSCLC have epidermal growth factor receptor (EGFR) mutations and are promisingly treated with tyrosine kinase inhibitors (TKIs), such as erlotinib or gefitinib [36], [37], [38], [39].…”

Section: Introductionmentioning

confidence: 99%

PI3K Inhibition Augments the Therapeutic Efficacy of a 3a-aza-Cyclopenta[α]indene Derivative in Lung Cancer Cells

Sanjiv

Chen

Kakadiya

et al. 2014

Translational Oncology

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The synergistic targeting of DNA damage and DNA repair is a promising strategy for the development of new chemotherapeutic agents for human lung cancer. The DNA interstrand cross-linking agent BO-1509, a derivative of 3a-aza-cyclopenta[α]indene, was synthesized and combined with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 to treat human lung cancer cells. Our results showed that the BO-1509 and LY294002 combination synergistically killed lung cancer cells in culture and also suppressed the growth of lung cancer xenografts in mice, including those derived from gefitinib-resistant cells. We also found that LY294002 suppressed the induction of several DNA repair proteins by BO-1509 and inhibited the nuclear translocation of Rad51. On the basis of the results of the γH2AX foci formation assays, LY294002 apparently inhibited the repair of DNA damage that was induced by BO-1509. According to the complete blood profile, biochemical enzyme analysis, and histopathologic analysis of major organs, no apparent toxicity was observed in mice treated with BO-1509 alone or in combination with LY294002. Our results suggest that the combination of a DNA cross-linking agent with a PI3K inhibitor is a feasible strategy for the treatment of patients with lung cancer.

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“…The results suggested a poor prognosis regarding survival in patients with an abnormal p53 status. Nevertheless the role of p53 in the treatment algorithm remains uncertain [17], as there are no prospective evaluations.…”

Section: Apoptosismentioning

confidence: 99%