The study of primary and acquired resistance to first-line osimertinib to improve the outcome of EGFR-mutated advanced Non-small cell lung cancer patients: the challenge is open for new therapeutic strategies

Ferro, Alessandra; Marinato, Gian Marco; Mulargiu, Cristiana; Marino, Monica; Pasello, Giulia; Guarneri, Valentina; Bonanno, Laura

doi:10.1016/j.critrevonc.2024.104295

Cited by 6 publications

(3 citation statements)

References 200 publications

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“…Due to the molecular heterogeneity of NSCLC, the resistance mechanisms to third-generation TKIs are complicated and not fully understood. Acquired resistance to EGFR TKIs can be broadly categorized into EGFR -dependent (on-target) and EGFR -independent (off-target) ( 12 , 13 ). Relevant therapeutic options have been found to prolong clinical benefits.…”

Section: Discussionmentioning

confidence: 99%

Case report: Sustained remission after combined sintilimab, anti-VEGF therapy, and chemotherapy in a patient with non-small cell lung cancer harboring acquired EGFR 19Del/T790M/cis-C797S mutation resistance

He,

Tong,

Yang

et al. 2024

Front. Oncol.

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Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are highly effective against tumors harboring the T790M mutation. However, patients treated with these inhibitors ultimately develop resistance, and the most common mechanism is the emergence of the EGFR C797S mutation. Few treatment regimens have been reported for this condition. In this report, we present a successful combination treatment with the programmed cell death 1 (PD-1) inhibitor sintilimab, anti-vascular endothelial growth factor (VEGF) therapy, and chemotherapy with pemetrexed and cisplatin in a patient with non-small cell lung cancer (NSCLC) who developed acquired resistance with EGFR 19 exon deletion (19Del)/T790M/cis-C797S mutation following progression with ametinib therapy. This regimen was well tolerated, and the patient has remained progression-free for 15 months. Our case provides clinical evidence that the combination of PD-1 inhibitor, anti-VEGF therapy, and chemotherapy may be an efficacious therapeutic strategy for NSCLC patients with acquired EGFR 19Del/T790M/cis-C797S mutation resistance following progression with EGFR TKI therapy.

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Section: Discussionmentioning

confidence: 99%

Case report: Sustained remission after combined sintilimab, anti-VEGF therapy, and chemotherapy in a patient with non-small cell lung cancer harboring acquired EGFR 19Del/T790M/cis-C797S mutation resistance

He,

Tong,

Yang

et al. 2024

Front. Oncol.

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“…Various known mechanisms include EGFR mutations (G719X, G796X, C797S) and wild-type EGFR amplification [ 10 ]. EGFR-independent factors like histological changes, alternative pathways (c-Met, HER2 amplification, Activation of IGF1R), NRAS/KRAS mutations, and oncogenic fusion genes (RET, ALK, BRAF) also contribute [ 11 ]. Still, around 40-50% of resistance mechanisms remain unclear [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

circ_PPAPDC1A promotes Osimertinib resistance by sponging the miR-30a-3p/ IGF1R pathway in non-small cell lung cancer (NSCLC)

Tang,

Liu,

Zhang

et al. 2024

Mol Cancer

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Background Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. Methods Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. Results The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. Conclusions Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance. Graphical Abstract

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“…Ongoing research is aimed at understanding the mechanisms of TKI resistance and developing innovative strategies. The study of primary and acquired resistance to TKIs, particularly in EGFR-mutated NSCLC, remains a critical area of research to improve patient outcomes [ 14 ]. The combination of TKIs with other agents is becoming increasingly important, and next-generation TKIs such as osimertinib for EGFR T790M mutations offer significant advances in the treatment of resistant NSCLC [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Multidrug-Resistant Profiles in Non-Small Cell Lung Carcinoma Patient-Derived Cells: Implications for Personalized Approaches with Tyrosine Kinase Inhibitors

Dinić,

Dragoj,

Jovanović Stojanov

et al. 2024

Cancers

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The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, potentially triggering MDR. The aim of our study was to evaluate the response of 17 patient-derived NSCLC cultures to 10 commonly prescribed TKIs and to correlate these responses with patient mutational profiles. Using an ex vivo immunofluorescence assay, we analyzed the expression of the MDR markers ABCB1, ABCC1, and ABCG2, and correlated these data with the genetic profiles of patients for a functional diagnostic approach. NSCLC cultures responded differently to TKIs, with erlotinib showing good efficacy regardless of mutation burden or EGFR status. However, the modulation of MDR mechanisms by erlotinib, such as increased ABCG2 expression, highlights the challenges associated with erlotinib treatment. Other TKIs showed limited efficacy, highlighting the variability of response in NSCLC. Genetic alterations in signaling pathways associated with drug resistance and sensitivity, including TP53 mutations, likely contributed to the variable responses to TKIs. The relationships between ABC transporter expression, gene alterations, and response to TKIs did not show consistent patterns. Our results suggest that in addition to mutational status, performing functional sensitivity screening is critical for identifying appropriate treatment strategies with TKIs. These results underscore the importance of considering drug sensitivity, off-target effects, MDR risks, and patient-specific genetic profiles when optimizing NSCLC treatment and highlight the potential for personalized approaches, especially in early stages.

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The study of primary and acquired resistance to first-line osimertinib to improve the outcome of EGFR-mutated advanced Non-small cell lung cancer patients: the challenge is open for new therapeutic strategies

Cited by 6 publications

References 200 publications

Case report: Sustained remission after combined sintilimab, anti-VEGF therapy, and chemotherapy in a patient with non-small cell lung cancer harboring acquired EGFR 19Del/T790M/cis-C797S mutation resistance

Case report: Sustained remission after combined sintilimab, anti-VEGF therapy, and chemotherapy in a patient with non-small cell lung cancer harboring acquired EGFR 19Del/T790M/cis-C797S mutation resistance

circ_PPAPDC1A promotes Osimertinib resistance by sponging the miR-30a-3p/ IGF1R pathway in non-small cell lung cancer (NSCLC)

Multidrug-Resistant Profiles in Non-Small Cell Lung Carcinoma Patient-Derived Cells: Implications for Personalized Approaches with Tyrosine Kinase Inhibitors

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