Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going

Russo, Alessandro; Franchina, Tindara; Ricciardi, Giuseppina Rosaria Rita; Smiroldo, Valeria; Picciotto, Maria; Zanghì, Mariangela; Rolfo, Christian; Adamo, Vincenzo

doi:10.1016/j.critrevonc.2017.07.003

Cited by 89 publications

(60 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Targeting the epidermal growth factor receptor (EGFR) tyrosine kinase with small‐molecule EGFR tyrosine kinase inhibitors (EGFR‐TKIs) represents a major advance in the targeted therapy of non–small cell lung cancer (NSCLC) carrying activating EGFR mutations. Hence, the development of EGFR‐TKIs has progressed rapidly from the initial first‐generation (eg, gefitinib and erlotinib), to the second‐generation (eg, afatinib), and now the third‐generation (eg, osimertinib [AZD9291 or TAGRISSO; AstraZeneca]) agents . However, the major challenge in the clinic is the emergence of acquired resistance to these EGFR‐TKIs, limiting the long‐term benefit to patients …”

Section: Introductionmentioning

confidence: 99%

“…Hence, the development of EGFR‐TKIs has progressed rapidly from the initial first‐generation (eg, gefitinib and erlotinib), to the second‐generation (eg, afatinib), and now the third‐generation (eg, osimertinib [AZD9291 or TAGRISSO; AstraZeneca]) agents . However, the major challenge in the clinic is the emergence of acquired resistance to these EGFR‐TKIs, limiting the long‐term benefit to patients …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Overcoming acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589)

Zang

Qian

Zong

et al. 2020

Cancer

View full text Add to dashboard Cite

BACKGROUND:The major clinical obstacle that limits the long-term benefits of treatment with osimertinib (AZD9291) in patients with epidermal growth factor receptor-mutant non-small cell lung cancer is the development of acquired resistance. Therefore, effective strategies that can overcome acquired resistance to osimertinib are urgently needed. The authors' current efforts in this direction have identified LBH589 (panobinostat), a clinically used histone deacetylase inhibitor, as a potential agent in overcoming osimertinib resistance. METHODS: Cell growth and apoptosis in vitro were evaluated by measuring cell numbers and colony formation and by detecting annexin V-positive cells and protein cleavage, respectively. Drug effects on tumor growth in vivo were assessed with xenografts in nude mice. Alterations of tested proteins in cells were monitored with Western blot analysis. Gene knockout was achieved using the CRISPR/ Cas9 technique. RESULTS: The combination of LBH589 and osimertinib synergistically decreased the survival of different osimertinibresistant cell lines, including those harboring C797S mutations, with greater inhibition of cell colony formation and growth. The combination enhanced the induction of apoptosis in osimertinib-resistant cells. Importantly, the combination effectively inhibited the growth of osimertinib-resistant xenograft tumors in nude mice. Mechanistically, the combination of LBH589 and osimertinib enhanced the elevation of Bim in osimertinib-resistant cells. Knockout of Bim in osimertinib-resistant cells substantially attenuated or abolished apoptosis enhanced by the LBH589 and osimertinib combination. These results collectively support a critical role of Bim elevation in the induction of apoptosis of osimertinib-resistant cells for this combination. CONCLUSIONS: The current findings provide strong preclinical evidence in support of the potential for LBH589 to overcome osimertinib resistance in the clinic.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overcoming acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589)

Zang

Qian

Zong

et al. 2020

Cancer

View full text Add to dashboard Cite

show abstract

“…A T790M mutant patient treated with olmutinib acquired the C797S mutation suggesting that the mechanism of action of olmutinib is similar to osimertinib [108]. Several other small molecule EGFR inhibitors have also been synthesized and they are reviewed elsewhere [109][110][111][112].…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

View full text Add to dashboard Cite

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.

show abstract

“…Recently, osimertinib has been shown to exert remarkable effects against untreated EGFR mutation-positive advanced NSCLC as well as those with EGFR-TKI-sensitizing and EGFR T790M resistance mutations [4]. This third generation TKIs can bind irreversibly to the EGFR kinase by targeting the cystine-797 residue in the ATP binding site via covalent bond formation and a phase 3 trial revealed prolonged progression-free survival with a similar safety profile and lower rates of serious adverse events compared to standard EGFR-TKIs [5]. Based on these results, osimertinib is now a key drug for the first line treatment for patients with EGFR-mutated NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Tumour Content Ratio Matters for Detecting Epidermal Growth Factor Receptor Mutation by Cobas Test in Small Biopsies; a Retrospective Study

Kogo

Fujimoto

Hosoya

et al. 2019

Preprint

View full text Add to dashboard Cite

Background Recent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR -mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing Materials and Methods We examined 132 patients with EGFR -mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR -positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide. Results The positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection. Conclusion Cobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.

show abstract

Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going

Cited by 89 publications

References 85 publications

Overcoming acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589)

Overcoming acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589)

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Tumour Content Ratio Matters for Detecting Epidermal Growth Factor Receptor Mutation by Cobas Test in Small Biopsies; a Retrospective Study

Contact Info

Product

Resources

About