Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis
Phuoc T. TranEmelyn H. ShroffTimothy F. BurnsSaravanan ThiyagarajanSandhya DasTahera ZabuawalaJoy ChenYoon-Jae ChoRichard LuongPablo TamayoTarek SalihKhaled AzizStacey J. AdamSilvestre VicentCarsten H. NielsenNadia WithofsE. Alejandro Sweet‐CorderoSanjiv S. GambhirCharles M. RudinDean W. Felsher
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Abstract:
KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with KrasG12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.Keywords:
Senescence
To explore the relationship between the expression of Bax gene and oncogenesis , development and prognosis of lung cancer.The expression level of Bax gene products was detected in 124 human non-small cell lung cancer by immunohistochemistry labelled-streptavidin-biotin methods.The expressional level of Bax products in lung cancer tissues (53. 76 %) was significantly lower than that in the normal tissues adjacent to lung cancer (75. 51 %) and normal lung tissues (74. 97 %) ( P < 0. 01) . The expressional level of Bax products was closely related with P-TNM stage , the size of primary tumor and lymph node metastasis ( P < 0. 01 or P < 0. 05) ; but not to histological classification , cell differentiation and site of the cancer , and age , sex of the patients and smoking or not ( P > 0. 05) . The five-year survival rate in patients with high Bax expression was significantly higher than that in patients with low Bax expression ( P < 0. 01) .Abnormal expression of Bax gene may play an important role in the oncogenesis , development and prognosis of lung cancer. Bax gene may be involved in the oncogenesis , development and metastasis of lung cancer.
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e19324 Background: KRAS G12C mutations are present in 15% of non-small cell lung cancer (NSCLC) and have recently been shown to confer sensitivity to KRAS(G12C) inhibitors. This study aims to assess the clinical features and outcomes with KRAS G12C mutant NSCLC in a real-world setting. Methods: Patients enrolled in an Australian prospective cohort study, Thoracic Malignancies Cohort (TMC), between July 2012 to October 2019 with metastatic or recurrent non-squamous NSCLC, with available KRAS test results, and without EGFR, ALK, or ROS1 gene aberrations, were selected. Data was extracted from TMC and patient records. Clinicopathologic features, treatment and overall survival was compared for KRAS wildtype ( KRAS WT ) and KRAS mutated ( KRAS mut ) patients, and between KRAS G12C ( KRAS G12C ) and other ( KRAS other ) mutations. Results: Of 1386 patients with non squamous NSCLC, 1040 were excluded for: non metastatic or recurrent (526); KRAS not tested (356); ALK, EGFR or ROS1 positive (154); duplicate (4). Of 346 patients analysed, 202 (58%) were KRAS WT and 144 (42%) were KRAS mut , of whom 65 (45%) were KRAS G12C . 100% of pts with KRAS G12C were smokers, compared to 92% of KRAS other and 83% of KRAS WT . The prevalence of brain metastases over entire follow-up period was similar between KRAS mut and KRAS WT (33% vs 40%, p = 0.17), and KRAS G12C and KRAS other (40% vs 41%, p = 0.74). Likewise, there was no difference in the proportion of patients receiving one or multiple lines of systemic therapy. Overall survival (OS) was also similar between KRAS mut and KRAS WT (p = 0.54), and KRAS G12C and KRAS other (p = 0.39). Conclusions: In this real-world prospective cohort, patients had comparable clinical features regardless of having a KRAS mut , KRAS G12C or KRAS other mutation, or being KRAS WT . Treatment and survival were also similar between groups. While not prognostic, KRAS G12C may be an important predictive biomarker as promising KRAS G12C covalent inhibitors continue to be developed.
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Abstract Background : KRAS is the most frequently mutated oncogene in cancer, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in colorectal (CRC) and non-small-cell lung cancer (NSCLC) tested in a clinical certified laboratory. Methods : CRC and NSCLC samples submitted for KRAS testing between 2017 and 2019 were reviewed. CRC samples were tested for KRAS and NRAS by pyrosequencing, while NSCLC samples were submitted to next generation sequencing of KRAS, NRAS, EGFR, and BRAF. Results : The dataset comprised 4,897 CRC and 4,686 NSCLC samples. Among CRC samples, KRAS was mutated in 2,354 (48.1%). Most frequent codon 12 mutations were G12D in 731 samples (15.2%) and G12V in 462 (9.6%), followed by G12C in 167 (3.4%). KRAS mutations were more frequent in females than males (p=0.003), however this difference was exclusive of non-G12C mutants (p<0.001). KRAS mutation frequency was lower in the South and North regions (p=0.003), but again KRAS G12C did not differ significantly (p=0.80). In NSCLC, KRAS mutations were found in 1,004 samples (21.4%). As opposed to CRC samples, G12C was the most common mutation in KRAS, in 346 cases (7.4%). The frequency of KRAS G12C was higher in the South and Southeast regions (p=0.012), and lower in patients younger than 50 years (p<0.001). KRAS G12C mutations were largely mutually exclusive with other driver mutations; only 11 NSCLC (3.2%) and 3 CRC (1.8%) cases had relevant co-mutations. Conclusions : KRAS G12C presents in frequencies higher than several other driver mutations, represent a large volume of patients in absolute numbers. KRAS testing should be considered in all CRC and NSCLC patients, independently of clinical or demographic characteristics.
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Lung cancer is the leading cause of tumor-related death,its incidence and mortality are both ahead of the disease spectrum.Cigarette smoking was identified as the single most predominant cause of the lung cancer epidemic,but the other factors were found,including radioactive substances,asbestos,metal and nutrition factors.Aberrant DNA methylation effects in lung cancer illustrates the mechanism by which environmental factors may interact with key genes involved in tumour suppression and contribute the way how to influence lung cancer.With the continuous investigate on the mechanism of lung tumorigenesis,aberrant DNA methylation induced by environment factors will be a potential useful biomarker to diagnosis or prognosis of the disease.Some special gene methylation is closely related with lung cancer,and as an early common event in the tumorigenesis,it is very important to the early diagnosis of lung tumor.
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To explore the relationship between the Bcl-2 gene transcript expression and the oncogenesis , and development of lung cancer.The expression of Bcl-2 mRNA was detected in 31 human lung cancer tissues , para-cancer tissues , non-cancer tissues and 13 benign lesion tissues by Northern blot.(1) The expression level of the Bcl-2 mRNA in the cancer tissues was significantly higher than that in the non-cancer tissues and benign lesion tissues ( P < 0. 01) , but there was no significant difference among the cancer and para-cancer tissues ,non-cancer and benign lesion tissues , para-cancer ,non-cancer and benign lesion tissues either ( P > 0. 05). (2) The Bcl-2 expression in poor-differentiated lung cancers was significantly higher than that in moderate-well differentiated lung cancers. (3) No significant difference was observed in Bcl-2 expression in different histoclassification of the cancer and P-TNM stages of the cancer.There is an overexpression of Bcl-2 mRNA in lung cancer tissues , and it may be involved in the oncogenesis and development of lung cancer.
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Senescence
Cellular senescence
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Concomitant
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KRAS遺伝子変異は非小細胞肺癌を含むヒトの癌で頻度の高いがん遺伝子変異の一つである．発見から30年以上のKRAS変異陽性癌の治療法開発にもかかわらず，臨床的有用性を示す薬物は得られず，創薬不能な標的とされてきた．理由として，KRASとGTPの親和性は高く結合阻害は困難，KRASの下流シグナルや膜結合に必要な翻訳後修飾はいくつも平行しており，単一の経路や修飾反応の阻害では他の活性化が起こる，KRAS変異陽性癌は必ずしもKRASに生死が依存していないことなどが考えられる．2013年にGDP結合KRASに低分子化合物がはまるポケットが見出され，G12C変異KRASに限定的ながら，KRASを不活性なGDP結合型に非可逆的に固定する化合物が報告された．この発見に基づき，ソトラシブやアダグラシブなどのG12C特異的阻害剤が開発され，前者は2021年に米国で，2次治療以降のKRASG12C変異陽性非小細胞肺癌に対し迅速承認された．今後，G12C以外の直接阻害剤，G12C阻害剤との併用療法，耐性獲得後の対策，有効な患者選択のためのバイオマーカーなどについて，さらなる研究開発が待たれる．
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Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
Senescence
Proinflammatory cytokine
Malignant Transformation
Cellular senescence
Tumor progression
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Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR) network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients.
Senescence
Cellular senescence
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