Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Leonetti, Alessandro; Sharma, Sugandhi; Minari, Roberta; Perego, Paola; Giovannetti, Elisa; Tiseo, Marcello

doi:10.1038/s41416-019-0573-8

Cited by 900 publications

(872 citation statements)

References 109 publications

(274 reference statements)

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“…This result was not confirmed by a study from Labbé et al, that found no differences in ORR of patients treated with third generation TKIs, based on TP53 mutation status; this could be for the small size of the analyzed case series [28]. In the light of the paradigm shift brought by FLAURA trial [5], there is a need to identify which biomarkers could predict primary resistance to osimertinib as a first line therapy; if confirmed in a larger case series treated with third generation TKI in the first line, these results could help to better stratify patients, suggesting an EGFR-independent mechanism of resistance, as others have already highlighted [30].…”

Section: Discussionmentioning

confidence: 96%

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Canale

Petracci

Delmonte

et al. 2020

JCM

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Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor (EGFR)-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of TP53 mutations in predicting survival and response to EGFR-TKIs in EGFR-mutated NSCLC patients, to confirm, on an independent case series, our previous results. Methods: An independent retrospective cohort study was conducted, on a case series of 136 EGFR-mutated NSCLC patients receiving first or second generation TKIs as a first line therapy, and a smaller fraction of patients who acquired the T790M resistance mutation and were treated with third generation TKIs in the second or further line of treatment. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of the patients. Results: Forty-two patients (30.9%) showed a TP53 mutation. Considered together, TP53 mutations had no significant impact on time-to-event endpoints. Considering the different TP53 mutations separately, exon 8 mutations confirmed their negative effect on PFS (HR 3.16, 95% 1.59-6.28, p = 0.001). In patients who developed the T790M resistance mutation, treated with third generation TKIs, the TP53 exon 8 mutations predicted worse PFS (even though not statistically significant), and OS (HR 4.86, 95% CI: 1.25-18.90, p = 0.023). Conclusions: TP53 exon 8 mutations confirmed their negative prognostic impact in patients treated with first and second generation TKIs and demonstrated a role in affecting clinical outcome in patients treated with third generation TKIs.

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Section: Discussionmentioning

confidence: 96%

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Canale

Petracci

Delmonte

et al. 2020

JCM

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“…The L747P single mutation appears to be sufficient to confer resistance to erlotinib or gefitinib [98][99][100] if it occurs spontaneously but does not appear to arise in response to gefitinib/erlotinib treatment. Other mechanisms of resistance including mutations or upregulation of other pathways have also been documented [101,102] but we do not discuss them here.…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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“…3 The systemic therapies of NSCLC have revolutionized over recent years. Recently, the great success of the clinical application of epidermal growth factor receptor (EGFR) 4 and immune checkpoint 5,6 targeted therapies has significantly prolonged the overall survival rate of advanced NSCLC patients. However, owing to the low response rate and the intrinsic and acquired resistance, new treatment strategies are still an urgent demand.…”

Section: Introductionmentioning

confidence: 99%

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

Liu¹,

Yu²,

Zhou³

et al. 2020

OTT

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These authors contributed equally to this workBackground: Addiction to aerobic glycolysis is a common metabolic phenotype in human non-small cell lung cancer (NSCLC). The natural product Sinomenine (Sin) exhibits significant anti-tumor effects in various human cancers. However, the underlying mechanism remains elusive. Methods: The inhibitory effect of Sin on NSCLC cells was determined by MTS and soft agar assays. The glycolysis efficacy of NSCLC cells was examined by glucose uptake and lactate production. The activation of Akt signaling and the protein level of hexokinases II (HK2) were examined by immunoblot (IB), qRT-PCR, and immunohistochemical staining (IHC). The in vivo anti-tumor effect of Sin was validated by the xenograft mouse model. Results: We showed that HK2 is highly expressed in NSCLC tissues and cell lines. Depletion of HK2 suppressed cell viability, anchorage-independent colony formation, and xenograft tumor growth. Sinomenine exhibited a profound inhibitory effect on NSCLC cells by reducing HK2-mediated glycolysis both in vitro and in vivo. Ectopic overexpression of HK2 compromised these anti-tumor efficacies in sinomenine-treated NSCLC cells. Moreover, we revealed that sinomenine decreased Akt activity, which caused the downregulation of HK2-mediated glycolysis. Knockdown of Akt reduced HK2 protein level and impaired glycolysis. In contrast, overexpression of constitutively activated Akt1 reversed this phenotype. Conclusion: This study suggests that targeting HK2-mediated aerobic glycolysis is required for sinomenine-mediated anti-tumor activity.

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Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Cited by 900 publications

References 109 publications

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

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