PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling.

Despite initial high response rates to first-line EGFR TKI, all non-small-cell lung cancer (NSCLC) with EGFR-activating mutation will ultimately develop resistance to treatment. Identification of resistance mechanisms is critical to adapt treatment and improve patient outcomes. Here, we show that a transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs.

[Targeting the spliceosome: A new therapeutic strategy to counteract chemotherapy resistance in lung cancer?].

Lung cancer is the first cancer-related cause of death worldwide. This is in partially due to therapeutic resistance, which occurs in around 70% of patients, especially those receiving platinum salts, the gold-standard chemotherapy. The massive deregulation of alternative transcript splicing processes observed in many cancers has led to the development of a new class of pharmacological agents aimed at inhibiting the activity of the splicing machinery (spliceosome).

Altered splicing of ATG16-L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer.

Despite the initial efficacy of using tyrosine kinase inhibitors of epidermal growth factor receptors (EGFR-TKIs) for treating patients with non-small cell lung cancer (NSCLC), resistance inevitably develops. Recent studies highlight a link between alternative splicing and cancer drug response. Therefore, we aimed to identify deregulated splicing events that play a role in resistance to EGFR-TKI.

Circular RNAs and RNA Splice Variants as Biomarkers for Prognosis and Therapeutic Response in the Liquid Biopsies of Lung Cancer Patients.

Lung cancer, including non-small cell lung carcinoma (NSCLC), is the most frequently diagnosed cancer. It is also the leading cause of cancer-related mortality worldwide because of its late diagnosis and its resistance to therapies. Therefore, the identification of biomarkers for early diagnosis, prognosis, and monitoring of therapeutic response is urgently needed.

A VEGF-A/SOX2/SRSF2 network controls VEGFR1 pre-mRNA alternative splicing in lung carcinoma cells.

The splice variant sVEGFR1-i13 is a truncated version of the cell membrane-spanning VEGFR1 receptor that is devoid of its transmembrane and tyrosine kinase domains. We recently showed the contribution of sVEGFR1-i13 to the progression and the response of squamous lung carcinoma to anti-angiogenic therapies. In this study, we identify VEGF165, a splice variant of VEGF-A, as a regulator of sVEGFR1-i13 expression in these tumors, and further show that VEGF cooperates with the transcription factor SOX2 and the splicing factor SRSF2 to control sVEGFR1-i13 expression.

[Nuclear EGFR: a new mode of oncogenic signalling in cancer].

EGFR (Epidermal Growth Factor Receptor) is one of the most studied molecules in biology. From its early identification and cloning to the discovery of its role in cancer, it has been at the forefront of our understanding of Receptor Tyrosine Kinase (RTK) and cell signals that induce homeostasis, but when overexpressed, facilitate tumorigenesis. While the biological functions of EGFR traditionally involve the activation of a signaling network from the plasma membrane that includes activation of the RAS/MAPK/ERK, PI3K/AKT and STATS pathways, a new mode of EGFR signaling has been progressively decoded in which membrane-associated EGFR is transported after endocytosis from cell surface to the nucleus through endocytosis, retrograde trafficking to the Golgi, the endoplasmic reticulum and the inner nuclear membrane through a series of proteic interactions.

VEGFb, a splice variant of VEGF-A, promotes lung tumor progression and escape from anti-angiogenic therapies through a β1 integrin/VEGFR autocrine loop.

Vascular endothelial growth factor-A (VEGF-A) is highly subjected to alternative pre-mRNA splicing that generates several splice variants. The VEGF and VEGFb families encode splice variants of VEGF-A that differ only at the level of six amino acids in their C-terminal part. The expression level of VEGF splice variants and their function as pro-angiogenic factors during tumor neo-angiogenesis have been well-described.

ARF promotes the degradation of the Epidermal Growth Factor Receptor by the lysosome.

Epidermal Growth Factor Receptor (EGFR) signaling regulates multiple cellular processes including proliferation, survival and apoptosis, and is attenuated by lysosomal receptor degradation. EGFR is a potent oncogene and activating mutations of EGFR are critical determinants of oncogenic transformation as well as therapeutic targets in non-small cell lung cancer. We previously demonstrated that wild type and mutant EGFRs repress the expression of the ARF tumor suppressor to promote the survival of lung tumor cells.

The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma.

Background: While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain.

Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI.

Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin.

Splice Variants of the RTK Family: Their Role in Tumour Progression and Response to Targeted Therapy.

Receptor tyrosine kinases (RTKs) belong to a family of transmembrane receptors that display tyrosine kinase activity and trigger the activation of downstream signalling pathways mainly involved in cell proliferation and survival. RTK amplification or somatic mutations leading to their constitutive activation and oncogenic properties have been reported in various tumour types. Numerous RTK-targeted therapies have been developed to counteract this hyperactivation.

Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival.

Epidermal growth factor receptor (EGFR) is a cell surface receptor that has an essential role in cell proliferation and survival, and overexpression of EGFR is a common feature of human cancers. In Non-small-cell lung cancer (NSCLC), activating mutations of EGFR have also been described. We recently showed that mutant EGFR-L858R inhibits the expression of the p14ARF tumor-suppressor protein to promote cell survival.

RNA splicing, cell signaling, and response to therapies.

Purpose Of Review: PremRNA alternative splicing is more a rule than an exception as it affects more than 90% of multiexons genes and plays a key role in proteome diversity. Here, we discuss some recent studies published in the extensively growing field linking RNA splicing and cancer.

Recent Findings: These last years, the development of high-throughput studies together with appropriate bioinformatic tools have led to the identification of new cancer-specific splicing patterns that allow to distinguish various cancer types, and provide new prognosis biomarkers.

A new function of the splicing factor SRSF2 in the control of E2F1-mediated cell cycle progression in neuroendocrine lung tumors.

The transcription factor E2F1 belongs to the E2F family and plays a crucial role during cell cycle progression and apoptosis. Ser/Arg-Rich (SR) proteins are a family of RNA-binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing events. We previously identified the SR protein SRSF2 as a new transcriptional target of E2F1 and demonstrated that both proteins cooperate to induce apoptosis in non-small cell lung carcinoma.

Abnormal expression of the pre-mRNA splicing regulators SRSF1, SRSF2, SRPK1 and SRPK2 in non small cell lung carcinoma.

Splicing abnormalities frequently occur in cancer. A key role as splice site choice regulator is played by the members of the SR (Ser/Arg-rich) family of proteins. We recently demonstrated that SRSF2 is involved in cisplatin-mediated apoptosis of human lung carcinoma cell lines.

p14(ARF) inhibits the growth of lung adenocarcinoma cells harbouring an EGFR L858R mutation by activating a STAT3-dependent pro-apoptotic signalling pathway.

Epidermal growth factor receptor (EGFR) stimulates proliferative and survival signals. Activating mutations of EGFR are involved in the aetiology and maintenance of the malignant phenotype of lung tumours. We previously described the frequent association of these mutations with the decreased expression of the p14(ARF) tumour suppressor, another common feature of lung cancer.