PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

Ferrara, Miriam Grazia; Martini, Maurizio; D’Argento, Ettore; Forcella, Chiara; Vita, Emanuele; Noia, Vincenzo Di; Sperduti, Isabella; Bilotta, Mirna; Ribelli, Marta; Damiano, P.; Cannella, Antonella; Stefani, Alessio; Pilotto, Sara; Carbone, Carmine; Piro, Geny; Milella, Michèle; Bria, Emilio

doi:10.1016/j.cllc.2020.12.008

Cited by 7 publications

(6 citation statements)

References 60 publications

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“…Additional coexisting mutations and the proportion of EGFR mutations can affect PFS ( 21 ), and immunohistochemical analyses of tumor tissue from NSCLC patients treated with first-line EGFR -TKIs have shown that co-occurring PTEN loss and IGFR overexpression correlated with poorer PFS and OS ( 22 ). In addition, the proapoptotic protein BIM and the negatively regulated apoptosis element of mTOR may account for the variable response of NSCLC patients to EGFR TKI therapy ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

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EGFR amplification is a putative resistance mechanism for NSCLC–LM patients with TKI therapy and is associated with poor outcome

Yang

Wen²,

Zhao³

et al. 2022

Front. Oncol.

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BackgroundLeptomeningeal metastases (LM) have become increasingly common in non-small cell lung cancer (NSCLC) patients who harbor epidermal growth factor receptor (EGFR) mutation treated with EGFR-TKI and are correlated with inferior prognosis. Evidence in prior research demonstrated that EGFR amplification was more likely presented in advanced clinical stages and was associated with worse survival. However, whether EGFR amplification is a prognostic marker in NSCLC–LM is still inconclusive.MethodsThis study enrolled patients diagnosed with NSCLC–LM from June 2019 to September 2021 and who had received previous EGFR-TKI at Guangdong Sanjiu Brain Hospital. Cerebrospinal fluid (CSF) samples were collected and subjected to targeted next-generation sequencing of 168 cancer-related genes. Clinical characteristics and overall survival (OS) were compared in patients with and without EGFR amplification.ResultsThis study enrolled 53 NSCLC–LM patients, all of whom had EGFR mutations. TP53 and EGFR amplifications are the two most frequent mutations in the study cohort, presenting at 72% (38 of 53) and 40% (21 of 53), respectively. The rate of EGFR amplification was much higher at the time of leptomeningeal progression than at initial diagnosis (p < 0.01). Karnoskfy performance status was poorer (p = 0.021), and CSF pressure was higher (p = 0.0067) in patients with EGFR amplification than those without. A multivariable Cox proportional hazard regression model showed that EGFR amplification was an independent prognostic factor for poorer OS (8.3 vs. 15 months; p = 0.017). The median OS was shorter in NSCLC–LM patients with mutated TP53 than those with wild-type TP53, but the difference was not statistically significant (10 vs. 17.3 months, p = 0.184).ConclusionsEGFR gene amplification could be a potential resistance mechanism to EGFR-TKI failure in NSCLC–LM and is associated with inferior clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

“…TKIs have shown that co-occurring PTEN loss and IGFR overexpression correlated with poorer PFS and OS (22). In addition, the proapoptotic protein BIM and the negatively regulated apoptosis element of mTOR may account for the variable response of NSCLC patients to EGFR TKI therapy (23).…”

Section: B Amentioning

confidence: 99%

EGFR amplification is a putative resistance mechanism for NSCLC–LM patients with TKI therapy and is associated with poor outcome

Yang

Wen²,

Zhao³

et al. 2022

Front. Oncol.

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“…Some of these microRNAs reduce carcinogenesis or promote apoptosis by targeting the mRNAs of proto-oncogenes and shutting them down, while others enhance the anti-apoptotic ability of tumor cells by down-regulating the expression of tumor suppressor genes. For instance, the cancer suppressor gene PTEN is controlled by a variety of microRNAs and affects the PI3K/AKT signaling pathway, which in turn affects the apoptotic process of tumor cells, it was proved that the inactivation of PTEN is a single of the important factors in the development of lung cancer ( 93 ). MiR-142-5p was up-regulated in NSCLC tissues and cells.…”

Section: Microrna Affects Lung Cancer Development Through the Pi3k/ak...mentioning

confidence: 99%

Advances in the role of microRNAs associated with the PI3K/AKT signaling pathway in lung cancer

Wang,

Zhang,

2023

Front. Oncol.

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Cancer has long been a topic of great interest in society and a major factor affecting human health. Breast, prostate, lung, and colorectal cancers are the top four tumor types with the greatest incidence rates in 2020, according to the most recent data on global cancer incidence. Among these, lung cancer had the highest fatality rate. Extensive research has shown that microRNAs, through different signaling pathways, play crucial roles in cancer development. It is considered that the PI3K/AKT signaling pathway plays a significant role in the development of lung cancer. MicroRNAs can act as a tumor suppressor or an oncogene by altering the expression of important proteins in this pathway, such as PTEN and AKT. In order to improve the clinical translational benefit of microRNAs in lung cancer research, we have generalized and summarized the way of action of microRNAs linked with the PI3/AKT signaling pathway in this review through literature search and data analysis.

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“…PTEN negatively regulates the PTEN/PI3K/Akt signaling pathway and regulates cell growth, apoptosis, and migration ( 92 ). Studies have shown that patients with EGFR mutations with PTEN deletions have significantly shorter PFS durations than those without PTEN deletions (6 vs. 18 months) ( 93 ). According to Xun et al ( 92 ), the deletion of PTEN in lung cancer promotes the carcinogenic function of STMN1 (overexpression of which is related to tumor growth, metastasis, and poor survival) through the PI3K/AKT pathway.…”

Section: Drug Resistance Mechanisms and Progress In The Use Of First-...mentioning

confidence: 99%

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

et al. 2022

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According to global cancer data, lung cancer was the leading cause of cancer-related death in 2020. With the diversification of treatment strategies, the survival outcomes of patients with advanced lung cancer have improved significantly, but the 5-year overall survival rate remains <20%. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for lung adenocarcinoma patients with EGFR-sensitive mutations; however, acquired drug resistance is inevitable. Osimertinib (a third-generation EGFR inhibitor) is the most commonly used drug for cancers with a secondary T790M mutation. Unfortunately, acquired drug resistance against third-generation drugs still emerges. The C797s mutation is the primary acquired resistance mechanism against Osimertinib. Research on fourth-generation EGFR-TKI drugs with a C797s mutation is currently at various experimental stages, and no drug has been approved for clinical use. In addition to the resistance mechanisms described above, HER2 amplification, MET amplification, PIK3A mutation, KRAS mutation, BRAF mutation, transformation to small cell lung cancer, transformation to lung squamous cell carcinoma, and EMT have been reported as mechanisms of acquired drug resistance to first-, second-and third-generation EGFR-TKIs. These mechanisms are noted in a relatively high proportion of tumors, but treatment options are limited. In recent years, immunotherapy has made progress in the treatment of several cancers, including advanced EGFR-mutated non-small cell lung cancer (NSCLC). Due to the relatively high frequency of EGFR mutation in patients with lung adenocarcinoma in China, an increased number of patients develop EGFR-TKI resistance, and subsequent treatment options are critical. This article reviews the mechanisms of drug resistance to different EGFR-TKIs and treatment progression, providing ideas for the follow-up treatment for EGFR-resistant patients.

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PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

Cited by 7 publications

References 60 publications

EGFR amplification is a putative resistance mechanism for NSCLC–LM patients with TKI therapy and is associated with poor outcome

EGFR amplification is a putative resistance mechanism for NSCLC–LM patients with TKI therapy and is associated with poor outcome

Advances in the role of microRNAs associated with the PI3K/AKT signaling pathway in lung cancer

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

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