Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance

Schrank, Zachary; Chhabra, Gagan; Lin, Leo; Iderzorig, Tsatsral; Osude, Chike; Khan, Nabiha; Kuckovic, Adijan; Singh, Sanjana; Miller, Ronald H.; Puri, Neelu

doi:10.3390/cancers10070224

Cited by 105 publications

(95 citation statements)

References 113 publications

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“…However, besides the high cost of therapy, the targeted drugs and immunotherapies benefit small and specific groups of NSCLC patients. This is true primarily because < 30% of all NSCLC patients show targetable mutations [19], while anti-PD-1 drugs are effective only in patients with tumors expressing PDL-1 on >50% of tumor cells [20]. Moreover, drug resistance during the course of treatment is a major limiting factor in targeted and immunotherapies.…”

Section: Research Papermentioning

confidence: 99%

Untitled

2020

Oncotarget

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Platinum-taxane combination chemotherapy still represents the standard of care for advanced non-small cell lung cancer (NSCLC) with no targetable driver mutations. However, the efficacy of these drugs has plateaued at 10-14 months primarily due to dose-limiting toxicity, chemoresistance, and metastasis. Here, we explored the effects of withaferin A (WFA) alone and in combination with paclitaxel (PAC) on the growth, proliferation, migration, and invasion of human NSCLC cells. We show that the sensitivity of H1299 and A549 cells to concomitant treatment with PAC and WFA was greater than that of either PAC or WFA alone. Using the combination index and dosereduction index, we demonstrated that various combinations (1:40, 1:20, 1:10) of PAC to WFA, respectively, were highly synergistic. In addition, PAC+WFA co-treatment synergistically inhibited colony formation, migration, invasion and increased the induction of apoptosis in H1299 and A549 cells. Interestingly, the synergism of PAC and WFA was not schedule-dependent but was enhanced when cells were pretreated with WFA indicating a chemo-sensitizing effect. Importantly, WFA was active against both PAC-sensitive (TS-A549) and PAC-resistant (TR-A549) cells both in vitro and in vivo. Mechanistically, WFA inhibits the proliferation of NSCLC cells via thiol oxidation. The effects of WFA were inhibited in the presence of N-acetyl cysteine and other thiol donors. Taken together, our results demonstrate the efficacy of WFA alone or alongside PAC on NSCLC cells and provide a strong rationale for further detailed testing in clinically relevant models for the development of PAC+WFA combination as an alternative therapeutic strategy for advanced NSCLC.

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Section: Research Papermentioning

confidence: 99%

Untitled

2020

Oncotarget

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“…Figure summarizes the concise mechanisms underlying the combination of gefitinib and metformin, investigated so far …”

Section: Combination Of Metformin With Small Molecular Inhibitorsmentioning

confidence: 99%

Novel application of metformin combined with targeted drugs on anticancer treatment

et al. 2018

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The success of targeted drug therapies for treating cancer patients has attracted broad attention both in the academic community and social society. However, rapidly developed acquired resistance is becoming a newly recognized major challenge to the continuing efficiency of these therapies. Metformin is a well‐known natural compound with low toxicity derived from the plant French lilac. Our previous work has highlighted research progress of the combination of clinically applied chemotherapies and metformin by different mechanisms. We have also launched a study to combine metformin with the small molecule targeted drug gefitinib to treat bladder cancer using intravesical administration. Thus, in this minireview, we summarize recent achievements combining metformin with various targeted therapies. This work directs the potential clinical future by selecting available cancer patients and providing precise medicine by the combination of metformin and targeted drugs to overcome resistance and enhance therapeutic efficacies.

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“…Unlike the previous marker, KRAS is associated with tobacco use, with only 5 to 10% of KRAS-mutant lung cancers arising in never or light smokers 6,8 . Current molecularly-targeted therapies can effectively target specific biomarkers, decreasing multiple undesirable side effects associated with cancer treatment 9 . EGFR mutations are the most well characterised and several NSCLC treatments based on it were already approved 9 .…”

Section: Introductionmentioning

confidence: 99%

“…Current molecularly-targeted therapies can effectively target specific biomarkers, decreasing multiple undesirable side effects associated with cancer treatment 9 . EGFR mutations are the most well characterised and several NSCLC treatments based on it were already approved 9 . Effective therapies targeting KRAS are yet to be developed, although it is an extremely relevant topic that is actively being researched 10 .…”

Section: Introductionmentioning

confidence: 99%

Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS

Pinheiro

Pereira

Dias

et al. 2019

Preprint

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EGFR and KRAS are the most frequently mutated genes in lung cancer, being active research topics in targeted therapy. Biopsy is the traditional method to genetically characterise a tumour. However, it is a risky procedure, painful for the patient, and, occasionally, the tumour might be inaccessible. This work aims to study and debate the nature of the relationships between imaging phenotypes and lung cancer-related mutation status. Until now, the literature has failed to point to new research directions, mainly consisting of results-oriented works in a field where there is still not enough available data to train clinically viable models. We intend to open a discussion about critical points and to present new possibilities for future radiogenomics studies. We conducted high-dimensional data visualisation and developed classifiers, which allowed us to analyse the results for EGFR and KRAS biological markers according to different combinations of input features. We show that EGFR mutation status might be correlated to CT scans imaging phenotypes, however, the same does not seem to hold true for KRAS mutation status. Also, the experiments suggest that the best way to approach this problem is by combining nodule-related features with features from other lung structures. 2/103/10 7/10 is balanced individually for each fold using SMOTE-NC, avoiding data leakage. After parameter optimisation, probabilistic outputs of each model with optimal parameters were analysed using the AUC of Receiver Operating Characteristic (ROC). ROC is a probability curve and AUC represents degree or measure of separability, telling how much model is capable of distinguishing between classes. The ROC curve is plotted with True Positive Rate (TPR) against the False Positive Rate (FPR), usually with TPR on the y-axis and FPR on the x-axis. Experimental DesignWe designed four experiments in order to test and compare which type of input features allow to achieve better performance in gene mutation status prediction. We first trained a model that took nodule-related radiomic features as input. Then, for direct comparison purposes and to allow a modular evaluation, we split the semantic data into three parts: nodule, non-nodule and hybrid. The first one contains only nodular information, the second one contains only information external to the nodule and the third one is the combination of both. The split can be seen in detail in Table 2 of the supplementary material. 10/10

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Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance

Cited by 105 publications

References 113 publications

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Novel application of metformin combined with targeted drugs on anticancer treatment

Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS

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