Synthetic lethality targeting LKB1 mutant and EGFR wild type human non-small cell lung cancer cells by glucose starvation and SGLT2 inhibition

SUMMARYIn this study, we aimed to discover novel therapeutic approaches targeting non-small cell lung cancer (NSCLC) patients without EGFR mutation. First, we found that mutations of EGFR and LKB1 are mutually exclusive in NSCLC. EGFR-WT/LKB1-mutant cells are resistant to EGFR inhibitor erlotinib but are highly susceptible to glucose starvation or SGLT2 inhibitor canagliflozin. Mechanistically, in these cells, glucose starvation causes suppression of AMPK and induction of oxidative stress, leading to cell death. Finally, canagliflozin effectively reduces tumor growth of EGFR-WT/LKB1-mutant NSCLC cells in the mice xenograft model. Our data thus demonstrate that synthetic lethality can be achieved by glucose starvation or SGLT2 inhibition in EGFR-WT/LKB1-mutant NSCLC.SIGNIFICANCEAt present, EGFR inhibitor-based targeted therapy can only benefit those non-small cell lung cancer (NSCLC) patients with EGFR mutation. Therefore, there is an urgent need to develop alternate targeted therapy for NSCLC with WT EGFR. In this study, we found that mutations of EGFR and LKB1 are mutually exclusive in NSCLC, and more importantly, synthetic lethality can be achieved in EGFR-WT/LKB1-mutant NSCLC cells with glucose starvation or SGLT2 inhibition. Since SGLT2 inhibitors such as canagliflozin are FDA-approved drugs for type II diabetes, our study thus points out a possibility of developing SGLT2 inhibitors as a targeted therapy for NSCLC patients with WT EGFR and mutant LKB1, which will benefit about 15-30% of NSCLC patients.HIGHLIGHTSEGFR and LKB1 mutations are mutually exclusive in NSCLCEGFR-WT/LKB1-mutant NSCLC cells are sensitive to cell death induced by glucose starvation and SGLT2 inhibitionGlucose starvation suppresses AMPK activity in LKB1-mutant NSCLC cellsSGLT2 inhibitor canagliflozin causes synthetic lethality in LKB1-mutant NSCLC cells

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miR-34c-3p targets CDK1 a synthetic lethality partner of KRAS in non-small cell lung cancer

Cancer Gene Therapy ◽

10.1038/s41417-020-00224-1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Francesco Palma ◽

Alessandra Affinito ◽

Silvia Nuzzo ◽

Giuseppina Roscigno ◽

Iolanda Scognamiglio ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Synthetic Lethality ◽

Small Cell ◽

In Vitro Assays ◽

Prognostic Impact ◽

Small Cell Lung ◽

Nsclc Patients

Abstract Lung cancer is still the leading cause of death by cancer worldwide despite advances both in its detection and therapy. Multiple oncogenic driver alterations have been discovered, opening the prospective for new potential therapeutic targets. Among them, KRAS mutations represent the most frequent oncogene aberrations in non-small cell lung cancer (NSCLC) patients with a negative prognostic impact, but effective therapies targeting KRAS are not well characterized yet. Here, we demonstrate that the microRNA miR-34c-3p is a positive prognostic factor in KRAS-mutated NSCLC patients. Firstly, looking at the TGCA dataset, we found that high miR-34c-3p expression correlated with longer survival of KRAS-mutated NSCLC patients. In vitro assays on immortalized and patient-derived primary NSCLC cells revealed that miR-34c-3p overexpression increased apoptosis and lowered proliferation rate in KRASmut cells. Computational analysis and in vitro assays identified CDK1, one of the most promising lethal targets for KRAS-mutant cancer, as a target of miR-34c-3p. Moreover, the combination of CDK1 inhibition (mediated by RO3306) and miR-34c-3p overexpression resulted in an additive effect on the viability of KRASmut-expressing cells. Altogether, our findings demonstrate that miR-34c-3p is a novel biomarker that may allow tailored treatment for KRAS-mutated NSCLC patients.

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Biomarker utilization in non-small cell lung cancer, are we treating after testing?

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.9609 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 9609-9609

Author(s):

Elias Makhoul ◽

Jong Taek Kim ◽

Wenjuan Zhang ◽

Jean Raphael Lopategui ◽

Ani Sarkis Balmanoukian ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Small Cell ◽

Molecular Testing ◽

Small Cell Lung ◽

Nsclc Patients

9609 Background: Targeted therapy in EGFR and ALK mutated non-small cell lung cancer (NSCLC) has been the standard of care for nearly a decade with subsequent FDA approvals for ROS1 and BRAF V600 mutated NSCLC occurring in 2016 and 2017. However, recent studies have shown suboptimal utilization of genomic profiling results in these patients. In 1 recent study of community oncologists, ~70% of EGFR/ALK+ patients received appropriate targeted therapy, while patients with other gene mutations (including BRAF and ROS1) only received targeted therapy ~30% of the time. Left unanswered was what patients were receiving instead and why. Additionally, it is unknown if this finding is generalizable to the academic setting. We aimed to investigate whether in our patient population, NSCLC patients with actionable mutations received associated FDA approved therapies and if not why. Methods: The pathology database was queried for all NSCLC with molecular testing (including qPCR, FISH and NGS) from 2009 to 2019. Patients with sensitizing EGFR, ALK, ROS1 or BRAF mutations that were detected after the first FDA approval for their respective targeted therapies were included for analysis with those lost to follow up subsequently excluded. Basic demographic and clinical variables were collected as well as treatment records. Results: 2160 NSCLC patients were evaluated (2160 EGFR, 1417 ALK, 810 ROS1, 589 BRAF). 468 patients were identified with targetable mutations (411 EGFR, 46 ALK, 5 ROS1, 6 BRAF). No patient had more than 1 targetable mutation. Of those patients, 248 were at an advanced stage and had clinical follow up (202 EGFR, 37 ALK, 4 ROS1, 5 BRAF). Of those patients 197/202 (97.5%), 33/37 (89.2%), 3/4 (75%) and 1/5 (20%) received EGFR, ALK, ROS1 or BRAF targeted therapy respectively. Across biomarkers 14/248 patients (5.6%) did not receive subsequent targeted therapy. 10 patients (5 EGFR, 3 ALK, 1 ROS1 and 1 BRAF) passed away before targeted therapy could be initiated. Physician choice and missed findings accounted for the remaining four cases. Conclusions: The vast majority of advanced NSCLC patients analyzed in this study received appropriate targeted therapy matched to genomic findings. The main reason (~4% of total cases) that patients did not receive therapy was due to rapidly progressive disease and death before it could be initiated. These findings are at odds with those published from the community setting. This may be due to multiple factors, including clinician education, ease of access to targeted therapies across patient populations and incomplete data in the previous study populations.

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Evaluation of the Lung Immune Prognostic Index in Non-Small Cell Lung Cancer Patients Treated With Systemic Therapy: A Retrospective Study and Meta-Analysis

Frontiers in Oncology ◽

10.3389/fonc.2021.670230 ◽

2021 ◽

Vol 11 ◽

Author(s):

Litang Huang ◽

Hedong Han ◽

Li Zhou ◽

Xi Chen ◽

Qiuli Xu ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Systemic Therapy ◽

Meta Analysis ◽

Prognostic Index ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

The lung immune prognostic index (LIPI) has been shown to be an important prognostic marker for various tumors. However, the prognostic value of LIPI among non-small cell lung cancer (NSCLC) patients treated with systemic therapy remains controversial. We aimed to evaluate survival status according to LIPI among NSCLC patients receiving different forms of systemic therapy at our institution. We also performed a meta-analysis of articles from PubMed and Embase to illustrate this question. For our cohort, we found that good LIPI was associated with better overall survival (OS) among 91 patients on immunotherapy, 329 patients on targeted therapy, and 570 patients on chemotherapy. For the meta-analysis, a total of eight studies with 8,721 patients were included. Pooled results showed that a higher LIPI (those with 1 or 2 factors) was associated with poor overall progression-free survival (PFS) (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.45−1.71) and OS (HR, 2.01; 95% CI, 1.75−2.31). Subgroup analyses showed that a higher LIPI was related to poor survival among patients prescribed different systemic therapies: immunotherapy (OS HR, 2.50; 95% CI, 1.99–3.13; PFS HR, 1.77; 95% CI, 1.56–2.01), chemotherapy (OS HR, 1.58; 95% CI, 1.34–1.86; PFS HR, 1.38; 95% CI, 1.23–1.55), and targeted therapy (OS HR; 2.15, 95% CI, 1.57–2.96; PFS HR, 1.60; 95% CI, 1.25–2.06). The study shows that the LIPI is a clinically significant prognostic factor for NSCLC patients receiving systemic therapy.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420209009.

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TARGETED THERAPY OF NON-SMALL-CELL LUNG CANCER PATIENTS: MOST COMMON ADVERSE EVENTS AND METHODS OF THEIR CORRECTIONS

Russian Journal of Oncology ◽

10.18821/1028-9984-2017-22-6-300-306 ◽

2017 ◽

Vol 22 (6) ◽

pp. 300-306

Author(s):

Elena V. Reutova ◽

K. P Laktionov ◽

M. S Ardzinba

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Serious Adverse Events ◽

Long Term Treatment ◽

Nsclc Patients

Major advances in the treatment of non-small-cell lung cancer (NSCLC) patients are associated with the targeted therapy. It is both highly effective in the presence of activating mutations in the tumor and generally well-tolerated. Serious adverse events are recorded much less than with chemotherapy. There are significant differences in the toxicity profile. Both early detection and proper and timely correction of complications of targeted therapies are necessary for the successful long-term treatment of metastatic NSCLC patients.

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Pretreatment platelet/lymphocyte ratio (PLR) is a significant predictive marker for EGFR targeted therapy in patients with non-small-cell lung cancer

10.21203/rs.2.12821/v1 ◽

2019 ◽

Author(s):

Kejun Liu ◽

Weiwei Zhang ◽

Qinquan Tan ◽

Guanming Jiang ◽

Jun Jia

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Lymphocyte Ratio ◽

Platelet Lymphocyte Ratio ◽

Nsclc Patients ◽

Egfr Tkis

Abstract Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutation is benefited from targeted therapy. There is no other superior predictive factor for targeted therapy except EGFR in the clinical. In this study, we analyzed the effect of pretreatment platelet/lymphocyte ratio (PLR) in NSCLC patients. In the present study, a total of 96 patients with EGFR mutations were included in this study. All patients received EGFR targeted therapy, until disease progression, unacceptable toxicity or other factors. The following evaluation was conducted about 3 days before initial treatment: detailed clinical history, physical examination, radiographic results, pathological diagnosis and laboratory parameters including complete blood cell counts and albumin levels. We found that pretreatment PLR is significantly associated to the PFS of NSCLC patients with EGFR targeted therapy. Patients in the PLR ≥190 group had shorter PFS than those in the PLR <190 group (P= 0.009). Furthermore, the 1-year PFS rate in the PLR ≥190 group were inferior to the low value group (P= 0.016). Multivariate analysis confirmed the role of PLR on predicting the efficacy of targeted therapy for advanced NSCLC. In addition, we found that PLR was also an predictive biomarker for grade 3/4 adverse events of diarrhea. In conclusion, high pretreatment PLR was an independent indicator for predicting a poor PFS for NSCLC patients receiving EGFR-TKIs treatment. Further studies are needed to identify the impact of PLR on results of EGFR-TKIs treatment.

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Anti-PD-1/PD-L1 Therapy for Non-Small-Cell Lung Cancer: Toward Personalized Medicine and Combination Strategies

Journal of Immunology Research ◽

10.1155/2018/6984948 ◽

2018 ◽

Vol 2018 ◽

pp. 1-17 ◽

Cited By ~ 48

Author(s):

Hongshu Sui ◽

Ningxia Ma ◽

Ying Wang ◽

Hui Li ◽

Xiaoming Liu ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Diagnostic Assays ◽

Programmed Death ◽

Companion Diagnostic ◽

Nsclc Patients

Lung cancer remains a leading cause of cancer-related mortality worldwide with the poor prognosis. Encouragingly, immune checkpoint blockade targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has dramatically changed the landscape for treatments in patients with non-small-cell lung cancer (NSCLC). However, only a small proportion of NSCLC patients responded to monotherapy of anti-PD-1/PDL1 agents; together, the development of resistance to anti-PD-1/PD-L1 therapy that leads to failure of anti-PD-1/PD-L1 therapy has significantly limited a broad applicability of the findings in clinical practices. Nowadays, several companion diagnostic assays for PDL1 expression have been introduced for identifying patients who may benefit the immunotherapy. In addition, results from clinical trials explored combinatory therapeutic strategies with conventional and/or targeted therapy reported a higher efficacy with an acceptable safety profile in NSCLC treatments, as compared to the monotherapy of these agents alone. In this review article, we summarized several anti-PD-1/PD-L1 agents licensed for NSCLC treatment, with a focus on predictive biomarkers and companion diagnostic assays for identification of NSCLC patients for immunotherapy anti-PD-1/PDL1 antibodies. Of a great interest, potentials of the combinatory therapy of anti-PD-1/PDL1 therapy with a conventional or targeted therapy, or other immunotherapy such as CAR-T cell therapy were emphasized in the article.

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Effects of a mucosal coating spray in non-small cell lung cancer patients with nasal mucositis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21160 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21160-e21160

Author(s):

Fang Wang ◽

Hui Liu ◽

Zhen Zeng ◽

Shasha Wang ◽

Haifeng Qin

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Oral Mucositis ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Oral Liquid ◽

Nsclc Patients

e21160 Background: Targeted therapy opens a new era in the treatment of non-small cell lung cancer (NSCLC). At the same time, it also faces a serious problem, that is, the adverse events brought by new drugs, which not only affect the quality of patients’ life, but may even endanger their lives. Nasal mucositis (NM) may cause significant discomfort for the patients, and even result in the interruption of treatment. Episil (mucosal coating spray) oral liquid is a preservative-free oral liquid gel that can be used for the management of pain associated with oral lesions of various etiologies. Our study prospectively assessed effects of mucosal coating spray oral liquid in NSCLC patients with NM. There is no similar studies at home and abroad. Methods: Our study enrolled 15 patients who experience nasal mucositis after targeted therapy (Table). We designed a specific questionnaire according to Oral Mucositis Daily QuestionnaireOMDQ), Oral Mucositis Assessment Scale (OMAS), and the Patient-Reported Oral Mucositis Symptom (PROMS) to evaluate the change of life quality in NSCLC patients. All the patients needed to complete the questionnaire included in the statistical analysis. Evaluations were made before and after 5 treatment days. Results: All the patients were evaluated. Among patients, 87% suffered from NM grade 2 and 33% were with bleeding at study start, quality of life scores improved significantly after 5 treatment days with mucosal coating spray. Only 1 patient’s pain score reduced not that well because of nonstandard medication. No drug-related adverse reactions were found. Conclusions: Mucosal coating spray can effectively improve the nasal mucositis caused by targeted therapy in NSCLC patients. It may provide a new and effective therapy strategy for them, but large sample and additional clinical trials are also needed, especially for bevacizumab as one agent of combination protocol.

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Combining radiomic phenotypes of non-small cell lung cancer with liquid biopsy data may improve prediction of response to EGFR inhibitors

Scientific Reports ◽

10.1038/s41598-021-88239-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bardia Yousefi ◽

Michael J. LaRiviere ◽

Eric A. Cohen ◽

Thomas H. Buckingham ◽

Stephanie S. Yee ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Precision Oncology ◽

Small Cell Lung ◽

Clinical Variables ◽

C Statistic ◽

Nsclc Patients

AbstractAmong non-small cell lung cancer (NSCLC) patients with therapeutically targetable tumor mutations in epidermal growth factor receptor (EGFR), not all patients respond to targeted therapy. Combining circulating-tumor DNA (ctDNA), clinical variables, and radiomic phenotypes may improve prediction of EGFR-targeted therapy outcomes for NSCLC. This single-center retrospective study included 40 EGFR-mutant advanced NSCLC patients treated with EGFR-targeted therapy. ctDNA data included number of mutations and detection of EGFR T790M. Clinical data included age, smoking status, and ECOG performance status. Baseline chest CT scans were analyzed to extract 429 radiomic features from each primary tumor. Unsupervised hierarchical clustering was used to group tumors into phenotypes. Kaplan–Meier (K–M) curves and Cox proportional hazards regression were modeled for progression-free survival (PFS) and overall survival (OS). Likelihood ratio test (LRT) was used to compare fit between models. Among 40 patients (73% women, median age 62 years), consensus clustering identified two radiomic phenotypes. For PFS, the model combining radiomic phenotypes with ctDNA and clinical variables had c-statistic of 0.77 and a better fit (LRT p = 0.01) than the model with clinical and ctDNA variables alone with a c-statistic of 0.73. For OS, adding radiomic phenotypes resulted in c-statistic of 0.83 versus 0.80 when using clinical and ctDNA variables (LRT p = 0.08). Both models showed separation of K–M curves dichotomized by median prognostic score (p < 0.005). Combining radiomic phenotypes, ctDNA, and clinical variables may enhance precision oncology approaches to managing advanced non-small cell lung cancer with EGFR mutations.

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