scholarly journals The Journey of an EGFR-Mutant Lung Adenocarcinoma through Erlotinib, Osimertinib and ABCP Immunotherapy Regimens: Sensitivity and Resistance

2019 ◽  
Vol 12 (3) ◽  
pp. 765-776 ◽  
Author(s):  
Albina Kibirova ◽  
Malcolm D. Mattes ◽  
Matthew Smolkin ◽  
Patrick C. Ma
Keyword(s):  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Egfr Mutant ◽  
Egfr Tkis ◽  
Guided Therapy

Patients with epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) have several EGFR targeting tyrosine kinase inhibitors (TKIs) available in frontline management. However, the disease will inevitably progress over time due to acquired resistance. Longitudinal tumor profiling for genomics guided therapy is indicated upon disease progression. It is a common scenario yet, when after failure of EGFR-TKIs, potentially actionable genomic alterations are lacking. Management of such patient is challenging with very limited options available. Combination of chemotherapy, anti-vascular/anti-angiogenic and immune-checkpoint inhibitors may become a salvage option for such patients. Here we describe a case of TKI refractory EGFR-mutant NSCLC successfully treated with carboplatin, paclitaxel, atezolizumab and bevacizumab combination with remarkable prompt tumor response.

scholarly journals DDIS-17. DEVELOPMENT OF BRAIN-PENETRANT EGFR INHIBITORS FOR CNS MALIGNANCIES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi66-vi66
Author(s):  
Jonathan Tsang ◽  
Lorenz Urner ◽  
Christopher Tse ◽  
Lynn Baufeld ◽  
Kym Faull ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Tumor Response ◽  
Growth Factor Receptor ◽  
Structure Activity ◽  
Superior Efficacy ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Cns Malignancies

Abstract The epidermal growth factor receptor (EGFR) is altered in nearly 60% of glioblastoma (GBM) tumors, however, EGFR tyrosine kinase inhibitors (TKIs) have failed to improve outcomes for patients with GBM. This can be attributed to the inability of clinically available EGFR TKIs (e.g., erlotinib, gefitinib, lapatinib, afatinib, cetuximab) to effectively cross the blood-brain-barrier (BBB) and reach adequate pharmacological levels for a tumor response. Herein, we performed a structure-activity relationship (SAR) to obtain EGFR TKIs with both high brain penetrance and potency against EGFR-activated GBM cells. From over 80 novel compounds synthesized, our lead EGFR TKI—JCN068—exhibited exceptional BBB penetration (350% brain to plasma) while also having optimal ADME properties (60% oral bioavailability, ~5 hr half-life, >100 µg/mL solubility, etc). Moreover, JCN068 demonstrated picomolar potency against purified EGFR kinase, 1000-fold selectivity for EGFR relative to other kinases, and nanomolar activity against EGFR-altered, GBM patient-derived cells in culture. Importantly, JCN068 demonstrated superior efficacy—with negligible toxicity—compared to clinically available small molecule EGFR TKIs (erlotinib and lapatinib) against multiple EGFR-altered patient-derived orthotopic GBM xenografts. Due to these excellent drug-like properties, JCN068 is currently progressing towards clinical development for EGFR-activated GBM patients.

scholarly journals Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

2010 ◽  
Vol 28 (2) ◽  
pp. 357-360 ◽  
Author(s):  
David Jackman ◽  
William Pao ◽  
Gregory J. Riely ◽  
Jeffrey A. Engelman ◽  
Mark G. Kris ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Somatic Mutations ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Definition Of ◽  
Egfr Tki ◽  
Egfr Tkis

Ten percent of North American patients with non–small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or WHO) while on continuous treatment with gefitinib or erlotinib within the last 30 days; and no intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of new therapy. The relatively simple definition proposed here will lead to a more uniform approach to investigating the problem of acquired resistance to EGFR TKIs in this unique patient population. These guidelines should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired resistance to gefitinib and erlotinib.

scholarly journals Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer

2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sebastian Michels ◽  
Carina Heydt ◽  
Bianca van Veggel ◽  
Barbara Deschler-Baier ◽  
Nuria Pardo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Third Generation ◽  
Met Amplification ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis

PURPOSE Third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

scholarly journals PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1679
Author(s):  
Nadiia Lypova ◽  
Susan M. Dougherty ◽  
Lilibeth Lanceta ◽  
Jason Chesney ◽  
Yoannis Imbert-Fernandez
Keyword(s):  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Small Cell Lung ◽  
Mechanisms Of Resistance ◽  
Autophagy Flux ◽  
Epidermal Growth ◽  
Egfr Tkis

Tyrosine kinase inhibitors (TKIs) targeting the kinase domain of the epidermal growth factor receptor (EGFR), such as erlotinib, have dramatically improved clinical outcomes of patients with EGFR-driven non-small cell lung carcinomas (NSCLCs). However, intrinsic or acquired resistance remains a clinical barrier to the success of FDA-approved EGFR TKIs. Multiple mechanisms of resistance have been identified, including the activation of prosurvival autophagy. We have previously shown that the expression and activity of PFKFB3—a known driver of glycolysis—is associated with resistance to erlotinib and that PFKFB3 inhibition improves the response of NSCLC cells to erlotinib. This study focuses on investigating the role of PFKFB3 in regulating erlotinib-driven autophagy to escape resistance to erlotinib. We evaluated the consequence of pharmacological inhibition of PFKFB3 on erlotinib-driven autophagy in NSCLC cells with different mutation statuses. Here, we identify PFKFB3 as a mediator of erlotinib-induced autophagy in NSCLCs. We demonstrate that PFKFB3 inhibition sensitizes NCSLCs to erlotinib via impairing autophagy flux. In summary, our studies uncovered a novel crosstalk between PFKFB3 and EGFR that regulates erlotinib-induced autophagy, thus contributing to erlotinib sensitivity in NSCLCs.

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