Inhibition of AKT1 signaling promotes invasion and metastasis of non-small cell lung cancer cells with K-RAS or EGFR mutations

Rao, Guanhua; Pierobon, Mariaelena; Kim, In Kyu; Hsu, Wei‐Hsun; Deng, Jianghong; Moon, Young-Wan; Petricoin, Emanuel F.; Zhang, Kun; Wang, Yisong; Giaccone, Giuseppe

doi:10.1038/s41598-017-06128-9

Cited by 70 publications

(57 citation statements)

References 57 publications

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“…Recently we showed that Akt1, the predominant Akt isoform in the PCa cells [7] and vascular cells [ 8 , 9 , 10 ] plays a dual, reciprocal role in tumor growth and metastasis [11] . Similar results have also been reported in four other types of cancer such as the breast [ 12 , 13 ], liver [14] , non-small cell lung [15] and head and neck [16] . Furthermore, a very recent study from our lab has indicated that the specific loss of Akt1 in endothelial cells promotes prostate cancer metastasis [17] .…”

Section: Introductionsupporting

confidence: 86%

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

Alwhaibi

Gao

Artham

et al. 2018

Heliyon

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Recent studies indicate a stage-specific, differential role for the oncogene Akt on various cancers. In prostate cancer (PCa), suppression of Akt activity in the advanced stages promoted transforming growth factor-β (TGFβ) pathway-mediated epithelial-to-mesenchymal transition (EMT) and metastasis to the lungs. In the current study, we performed Affymetrix analysis to compare the expression profile of microRNAs in the mouse prostate tissues collected at the prostatic inter-epithelial neoplasia (PIN) stage from Transgenic adenocarcinoma of the mouse (TRAMP)/Akt1+/+ versus TRAMP/Akt1–/– mice, and at the advanced stage from TRAMP/Akt1+/+ mice treated with triciribine (Akt inhibitor) versus DMSO-treated control. Our analysis demonstrates that in the early stage, Akt1 in the TRAMP prostate tumors express a set of miRNAs responsible for regulating cancer cell survival, proliferation, and tumor growth, whereas, in the advanced stages, a different set of miRNAs that promote EMT and cancer metastasis is expressed. Our study has identified novel Akt-regulated signature microRNAs in the early and advanced PCa and demonstrates their differential effects on PCa growth and metastasis.

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Section: Introductionsupporting

confidence: 86%

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

Alwhaibi

Gao

Artham

et al. 2018

Heliyon

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“…There are a few limitations in our study. Firstly, although the panel of driver genes used in this study was chosen based on ASCO guidelines 5 , we did not take into account mutations in other driver genes such as PIK3CA 58 , AKT1 59 and ERBB2 60 , previously reported to co-exist with those detected mutations and possibly having significant clinical impacts. Secondly, when comparing the mutation profiles of the Vietnamese cohorts with MSK-IMPACT and East Asian cohort, we selected patients with AC in late stages (stage III-IV) to exclude the confounding effect of histological subtypes and tumour stage that are varied among three cohorts.…”

Section: Discussionmentioning

confidence: 99%

Actionable Mutation Profiles of Non-Small Cell Lung Cancer patients from Vietnamese population

Dang

Tran²,

Tran³

et al. 2020

Sci Rep

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Comprehensive profiling of actionable mutations in non-small cell lung cancer (NSCLC) is vital to guide targeted therapy, thereby improving the survival rate of patients. Despite the high incidence and mortality rate of NSCLC in Vietnam, the actionable mutation profiles of Vietnamese patients have not been thoroughly examined. Here, we employed massively parallel sequencing to identify alterations in major driver genes (EGFR, KRAS, NRAS, BRAF, ALK and ROS1) in 350 Vietnamese NSCLC patients. We showed that the Vietnamese NSCLC patients exhibited mutations most frequently in EGFR (35.4%) and KRAS (22.6%), followed by ALK (6.6%), ROS1 (3.1%), BRAF (2.3%) and NRAS (0.6%). Interestingly, the cohort of Vietnamese patients with advanced adenocarcinoma had higher prevalence of EGFR mutations than the Caucasian MSK-IMPACT cohort. Compared to the East Asian cohort, it had lower EGFR but higher KRAS mutation prevalence. We found that KRAS mutations were more commonly detected in male patients while EGFR mutations was more frequently found in female. Moreover, younger patients (<61 years) had higher genetic rearrangements in ALK or ROS1. In conclusions, our study revealed mutation profiles of 6 driver genes in the largest cohort of NSCLC patients in Vietnam to date, highlighting significant differences in mutation prevalence to other cohorts. Lung cancer is the most common malignancy and the leading cause of cancer related deaths worldwide (18.4% of total cancer deaths), with non-small cell lung cancer (NSCLC) being the most common subtype, accounting for approximately 85% of all diagnosed cases 1,2. The majority of NSCLC patients display advanced disease when diagnosed and thus have poor prognosis 2,3. It is well established that acquired genetic alterations in certain driver genes result in tumour growth and invasiveness, and that patients harboring certain mutations may benefit from targeted therapies 4,5. Indeed, a randomized clinical trial reported that advanced NSCLC patients harboring activating mutations in EGFR, one of the major driver genes of NSCLC, exhibited longer progression-free period when treated with a tyrosine kinase inhibitor (TKI), gefitinib, compared to those treated with standard platinum based chemotherapy 6. However, those who were treated with TKI drugs can acquire secondary resistant mutations, in which case a new treatment regimen is needed to maintain therapeutic effect 7,8. In addition to EGFR, NSCLC patients carrying ALK or ROS1 rearrangement were shown to respond well to a different TKI drug,

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“… 12 However, Rao et al found that inhibition of AKT1 is associated with the increased migration and invasion of EGFR + NSCLC cells by regulating the AKT1 - Myristoylated alanine-rich C-kinase substrate (MARCKS)-LAMC2 feedback loop. 13 This study showed a conflicting role of AKT1 on metastatic NSCLC processes. Therefore, the accurate efficacy of AKT1 could not be evaluated in this report.…”

Section: Discussionmentioning

confidence: 86%

<p>Three Novel <em>EGFR</em> Mutations (750_758del, I759S, T751_I759delinsS) in One Patient with Metastatic Non-Small Cell Lung Cancer Responding to Osimertinib: A Case Report</p>

Lin

et al. 2020

OTT

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Generations of epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR -TKIs) can significantly improve the outcome of EGFR -positive NSCLC patients. However, acquired TKIs-resistant mutations are inevitable. Except the common EGFR alterations, more and more rare mutations are revealed by next-generation sequencing (NGS), the clinical significance of which are still unclear. Here, we report an advanced lung adenocarcinoma patient who harbored two novel EGFR exon 19 deletions (750_758del and I759S) at the beginning and exhibited a short response to icotinib for 7.0 months. Then, secondary resistance EGFR T751_I759delinsS occurred. Chemotherapy combined with bevacizumab and erlotinib was administered in turn but failed. Standard-dose osimertinib (80 mg daily) obtained durable clinical remission for 16 months, and high-dose osimertinib (160 mg daily) further prolonged the survival of 9 months after leptomeningeal metastases (LM) occurring. This study presented the first case of intractable terminal NSCLC in a patient with EGFR 750_758del, I759S and T751_I759delinsS mutations, who responded positively to osimertinib and achieved a prolonged OS of 52 months, providing a potential therapeutic option for the patients harboring these particular EGFR mutations.

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Inhibition of AKT1 signaling promotes invasion and metastasis of non-small cell lung cancer cells with K-RAS or EGFR mutations

Cited by 70 publications

References 57 publications

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

Modulation in the microRNA repertoire is responsible for the stage-specific effects of Akt suppression on murine neuroendocrine prostate cancer

Actionable Mutation Profiles of Non-Small Cell Lung Cancer patients from Vietnamese population

<p>Three Novel <em>EGFR</em> Mutations (750_758del, I759S, T751_I759delinsS) in One Patient with Metastatic Non-Small Cell Lung Cancer Responding to Osimertinib: A Case Report</p>

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