Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer

Yap, Timothy A.; Macklin-Doherty, Aislinn; Popat, Sanjay

doi:10.1016/j.ejca.2016.10.014

Cited by 36 publications

(30 citation statements)

References 76 publications

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“…This perhaps suggests that other ligands such as HB-EGF, betacellulin (BTC), amphiregulin and/or ligand-independent EGFR transactivation such as via ROS, GPCR and SFKs may be more important 8 , 46 – 49 . Indeed, we and others have recently shown that SFK mediate EGFR transactivation in a variety of disease states including cardiovascular diseases and cancer 20 , 50 . Thus, these studies highlight an important role for SFK in upstream EGFR signaling in pathological states.…”

Section: Discussionmentioning

confidence: 93%

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model

El-Hashim¹,

Khajah²,

Renno

et al. 2017

Sci Rep

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The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kδ/Akt and NF-κB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IκB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway-selective inhibitors for ERK1/2 (PD89059) and PI3Kδ/Akt (IC-87114) respectively, or an inhibitor of NF-κB (BAY11-7085) also reduced the OVA-induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors.

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Section: Discussionmentioning

confidence: 93%

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model

El-Hashim¹,

Khajah²,

Renno

et al. 2017

Sci Rep

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“…For EGFR -, ALK -, or BRAF -positive patients, the following principles based on experience with patients with EGFR -positive NSCLC were applied: Use of TKI beyond radiological progression until clinically relevant progression [ 29 , 71 , 72 , 73 ]. Dose adjustments to avoid intolerable side effects [ 74 ].…”

Section: Methodsmentioning

confidence: 99%

“…Use of TKI beyond radiological progression until clinically relevant progression [ 29 , 71 , 72 , 73 ].…”

Section: Methodsmentioning

confidence: 99%

Oncogenic driver mutations, treatment, and EGFR-TKI resistance in a Caucasian population with non-small cell lung cancer: survival in clinical practice

et al. 2017

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IntroductionOncogenic driver mutations activating EGFR, ALK, or BRAF in NSCLC predict sensitivity to specific tyrosine-kinase inhibitors (TKIs). We provide data on prevalence, treatment and survival of driver-mutation positive NSCLC in a predominantly Caucasian population in routine clinical practice.Patients and MethodsNSCLC patients diagnosed from 2006-2015 with an EGFR-test result were included (n=265). Testing for EGFR, ALK, or BRAF was performed if specific TKI therapy was considered. Case-control analyses of overall survival (OS) comparing driver-mutation positive and negative patients were performed.Results44 sensitizing EGFR mutations (17%), 8 ALK translocations (7%, n=111) and 3 BRAF mutations (8%, n=39) were detected in adenocarcinoma or adenosquamous carcinoma. We did not find mutations in tumors without an adenocarcinoma-component. More than 90% of inoperable driver-mutation positive patients received TKI-therapy. Case-control analysis revealed improved OS of driver-mutation positive patients (39.6 vs. 19.4 months, HR 0.51). OS was improved in stage IV patients but not in stage I-III patients.OS of EGFR-TKI treated patients was similar for 1st and 2nd-line EGFR-TKI treatment. Patients not treated with EGFR-TKI had no benefit in OS. Re-biopsies obtained at progression revealed an EGFR-T790M mutation in 73% (n=11). These patients responded to the 3rd-generation EGFR-TKI osimertinib.DiscussionTesting guided by predictive clinical parameters resulted in twice as high rates of mutation-positive patients than expected, and TKI treatment resulted in a strong long-term OS advantage.ConclusionTesting for driver mutations is feasible in routine clinical practice, and identifies patients who benefit from TKI-therapy. OS compares favorably with OS in clinical studies.

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“…RTOG 1306 is an ongoing phase II trial currently investigating locally advanced unresectable NSCLC of nonsquamous histology comparing induction targeted therapy, erlotinib for EGFR mutants and crizotinib for ALK positive patients, followed by conventional chemoradiation versus no targeted therapy. Although targeted therapy shows great promise, the biggest concern is acquired resistance at which point the therapy loses its efficacy (12). There is limited data in regards to concurrent SABR and targeted therapy, so it is difficult to say at this time if such a treatment course is appropriate for patients without risking undue toxicity from co-administration (13).…”

mentioning

confidence: 99%

Utility of stereotactic ablative radiotherapy/stereotactic body radiation therapy in the setting of oligometastatic non-small cell lung cancer

Song

Lü

2018

J. Thorac. Dis.

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Continuing EGFR inhibition beyond progression in advanced non-small cell lung cancer

Cited by 36 publications

References 76 publications

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model

Oncogenic driver mutations, treatment, and EGFR-TKI resistance in a Caucasian population with non-small cell lung cancer: survival in clinical practice

Utility of stereotactic ablative radiotherapy/stereotactic body radiation therapy in the setting of oligometastatic non-small cell lung cancer

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