Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer

Jin, Ying; Chen, Yamei; Tang, Huarong; Hubert, Shawna M.; Li, Qian; Hu, Xiao; Su, Dan; Xu, Haimiao; Fan, Yun; Yu, Xinmin; Chen, Qixun; Liu, Jinshi; Hong, Wei; Xu, Yujin; Deng, Huan; Zhu, Dapeng; Li, Pansong; Gong, Yuhua; Xia, Xuefeng; Gay, Carl M.; Zhang, Jianjun; Chen, Ming

doi:10.1158/1078-0432.ccr-21-1943

Cited by 55 publications

(43 citation statements)

References 71 publications

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“…3F). Notably, signaling pathways known to drive tumorigenesis in SCLC and currently investigated in targeted therapy trials (DLL3-targeting molecules for the NOTCH pathway or PI3KCA/AKT inhibitors for the MAPK pathway) were specifically implicated in relapsed CD56+CTC 19, 20 . These results suggest that overcoming relapse after first-line systemic treatment may require targeting these signaling pathways, as we speculate this gives a selective advantage for resurgent SCLC clones.…”

Section: Resultsmentioning

confidence: 99%

Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Cancer

Ricordel

Chaillot

Vlachavas

et al. 2022

Preprint

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Introduction: Circulating Tumor Cells (CTC) have been studied in various solid tumors. However, clinical utility of CTC in Small Cell Lung Cancer (SCLC) remains poorly understood. Most published studies are based on Cellsearch isolation methods that did not capture CTC undergoing epithelial-mesenchymal transition. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of living CTC from SCLC and decipher their genomic characteristics. Method: We conducted a monocentric prospective non-interventional study (CTC-CPC) from April 2016 to April 2021, including treatment-naive newly diagnosed SCLC. CD56+CTC were isolated from whole blood samples using an immunofluorescence-based method, at diagnosis and relapse after first-line treatment. Whole-exome-sequencing (WES) was performed on isolated CTC, matched PBMC and tumor biopsies for genomic characterization. In addition, CTC Derived Xenografts (CDXs) were generated and submitted to RNA-sequencing for sub-type classification (ASCL1, POU2F3, YAP1, NEUROD1). Results: On the 46 patients eligible for the study, numeration of CD56+CTC was performed for 33 patients at diagnosis. Phenotypic study confirms tumor lineage and tumorigenic properties of isolated cells for the 4 patients analyzed with WES. Notably, CDX model derived from CD56+CTC was successfully classified with an ASCL1 transcriptomic profile. WES of CD56+CTC and matched tumor biopsy reveal common genomic alteration and biological pathway frequently impaired in SCLC. Moreover, CD56+CTC are characterized by a high mutation load and a unique mutational signature. High numeration of CD56+CTC (>7/mL) at diagnosis was associated with ES-SCLC. Finally, comparing genomic features of diagnosis and relapse CD56+CTC, we identify common altered oncogenic pathways (e.g. DLL3 or MAPK pathway) that are currently investigated in targeted therapy trials. Conclusions: We report a versatile and easy-to-use method of CD56+CTC detection for newly diagnosed SCLC. Isolated CD56+CTC conserve tumorigenic properties and can be used for further biological applications. Numeration of CD56+CTC at diagnosis is correlated with disease extension. Finally, genomic analysis suggests that studying CD56+CTC at relapse might help to identify oncologic pathways that seeds tumor resistance to first-line treatment.

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Section: Resultsmentioning

confidence: 99%

Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Cancer

Ricordel

Chaillot

Vlachavas

et al. 2022

Preprint

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“…Note that the repurposing of existing drugs, such as tyrosine kinase inhibitors, Hedgehog signaling inhibitors, anti-apoptotic inhibitors, and anti-angiogenesis agents, has not had a meaningful clinical impact in treating SCLCs [ 13 , 39 , 40 ]. Gene mutations (e.g., PIK3CA , PTEN , and RICTOR ) and activation of the PI3K/AKT/mTOR have been reported in genomic and proteomic profiling studies of SCLC tumor samples; however, there have been notable discrepancies in the results, due perhaps to relatively small sample sizes, differences in population (e.g., race, naïve or chemo-resistant) and sequencing techniques [ 8 , 10 , 12 , 41 ]. Nevertheless, the effectiveness of PTEN inactivation in accelerating SCLC in genetic mutant mouse models suggests that the PTEN-associated signaling pathway is a strong therapeutic pathway for SCLC, as long as predictive biomarkers can be identified [ 15 , 16 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

AKT phosphorylation as a predictive biomarker for PI3K/mTOR dual inhibition-induced proteolytic cleavage of mTOR companion proteins in small cell lung cancer

2022

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Background Constitutive activation of PI3K signaling has been well recognized in a subset of small cell lung cancer (SCLC), the cancer type which has the most aggressive clinical course amongst pulmonary tumors. Whereas cancers that acquire a mutation/copy gain in PIK3CA or loss of PTEN have been implicated in enhanced sensitivity to inhibitors targeting the PI3K/AKT/mTOR pathway, the complexities of the pathway and corresponding feedback loops hamper clear predictions as to the response of tumors presenting these genomic features. Methods The correlation between the expression profile of proteins involved in the PI3K/AKT/mTOR signaling and cell viability in response to treatment with small molecule inhibitors targeting isoform-specific PI3Ks, AKT, and mTOR was assessed in 13 SCLC cancer cell lines. Athymic nude mice were used to determine the effect of PI3K/mTOR dual inhibition on the growth of xenograft SCLC tumors in vivo. The activation of caspase signaling and proteolytic cleavages of mTOR companion proteins were assessed using recombinant caspases assays and Western blot analyses. Results Our results indicate that the sensitivity of these SCLC cell lines to GSK2126458, a dual PI3K/mTOR inhibitor, is positively correlated with the expression levels of phosphorylated AKT (p-AKT) at Thr308 and Ser473. Inhibition of pan-class I PI3Ks or PI3K/mTOR dual inhibition was shown to induce proteolytic cleavage of RICTOR and RPTOR, which were respectively dependent on Caspase-6 and Caspase-3. A combination of a clinically approved PI3Kα-selective inhibitor and an mTORC1 inhibitor was shown to have synergistic effects in inducing the death of SCLC cells with high p-AKT. We observed no clear correlation between PTEN levels and the survival of SCLCs in response to PI3K/mTOR dual inhibition; however, PTEN depletion was shown to increase the susceptibility of low p-AKT SCLC cells to dual PI3K/mTOR inhibitor-induced cell death as well as the proteolytic cleavage of RICTOR. Conclusions These results suggest the level of p-AKT can be a companion diagnostic biomarker for the treatment of SCLC involving the combinational use of clinically approved isoform-specific PI3K and mTOR inhibitors.

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“…In a related report, it was pointed out that in the hyperglycemic mouse model, the high glucose environment can increase the expression of HIF-1α through glucose-responsive carbohydrate response element binding protein (ChREBP), which leads to an increase in the expression of HIF-1α [ 43 , 44 ]. In addition, it was found in hyperglycemic patients that the hypoxia-inducible factor 1α–6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) pathway and activation of the PI3K/AKT pathway was induced to increase the expression of HIF-1α [ 45 , 46 ]. An animal model of pancreatic cancer with hyperglycemia showed that HIF-1α is abundantly expressed in cancer cells [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

HIF-1α Expression Increases Preoperative Concurrent Chemoradiotherapy Resistance in Hyperglycemic Rectal Cancer

Huang

Chen

Huang

et al. 2022

Cancers

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Purpose: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced rectal cancer patients. However, the poor therapeutic efficacy of CCRT was found in rectal cancer patients with hyperglycemia. This study investigated how hyperglycemia affects radiochemotherapy resistance in rectal cancer. Methods and Materials: We analyzed the correlation between prognosis indexes with hypoxia-inducible factor-1 alpha (HIF-1α) in rectal cancer patients with preoperative CCRT. In vitro, we investigated the effect of different concentrated glucose of environments on the radiation tolerance of rectal cancers. Further, we analyzed the combined HIF-1α inhibitor with radiation therapy in hyperglycemic rectal cancers. Results: The prognosis indexes of euglycemic or hyperglycemic rectal cancer patients after receiving CCRT treatment were investigated. The hyperglycemic rectal cancer patients (n = 13, glycosylated hemoglobin, HbA1c > 6.5%) had poorer prognosis indexes. In addition, a positive correlation was observed between HIF-1α expression and HbA1c levels (p = 0.046). Therefore, it is very important to clarify the relationship between HIF-1α and poor response in patients with hyperglycemia receiving pre-operative CCRT. Under a high glucose environment, rectal cancer cells express higher levels of glucose transport 1 (GLUT1), O-GlcNAc transferase (OGT), and HIF-1α, suggesting that the high glucose environment might stimulate HIF-1α expression through the GLUT1-OGT-HIF-1α pathway promoting tolerance to Fluorouracil (5-FU) and radiation. In the hyperglycemic rectal cancer animal model, rectal cancer cells confirmed that radiation exposure reduces apoptosis by overexpressing HIF-1α. Combining HIF-1α inhibitors was able to reverse radioresistance in a high glucose environment. Lower HIF-1α levels increased DNA damage in tumors leading to apoptosis. Conclusions: The findings here show that hyperglycemia induces the expression of GLUT1, OGT, and HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. HIF-1α inhibitors may be useful for development as CCRT sensitizers in patients with hyperglycemic rectal cancer.

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Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer

Cited by 55 publications

References 71 publications

Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Cancer

Genomic characteristics and clinical significance of CD56+ Circulating Tumor Cells in Small Cell Lung Cancer

AKT phosphorylation as a predictive biomarker for PI3K/mTOR dual inhibition-induced proteolytic cleavage of mTOR companion proteins in small cell lung cancer

HIF-1α Expression Increases Preoperative Concurrent Chemoradiotherapy Resistance in Hyperglycemic Rectal Cancer

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