Osimertinib

Osimertinib in Patients With Non–Small Cell Lung Cancer and Uncommon EGFR Mutations?

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The identification of genomic alterations within driver oncogenes has revolutionized the management of non–small cell lung cancer (NSCLC). Indeed, we now approach the twentieth anniversary of the discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC, a finding that catalyzed a new paradigm of precision medicine that has culminated in regulatory approvals of more than 20 targeted agents across various oncogenes. Importantly, insights into EGFR-mutant biology have continued to provide a roadmap for management of oncogene-driven NSCLC. Historically, EGFR-mutant NSCLC has been classified into 3 distinct subgroups. Classic EGFR mutations, which are characterized by exon 19 deletions or the exon 21 L858R substitution, account for approximately 80% of EGFR mutations and confer marked sensitivity to EGFR tyrosine kinase inhibitors.1 By contrast, EGFR exon 20 insertion mutations, which compose approximately 10% of EGFR mutations, are generally insensitive to treatment with early-generation EGFR inhibitors. Finally, uncommon or atypical EGFR mutations comprise a heterogeneous group of point mutations, deletions, or insertions within exons 18 to 25 and make up the remaining 10% to 15% of EGFR mutations.2 Currently, the optimal management of patients with these atypical mutations remains an open question. Okuma and colleagues3 present findings from the UNICORN study, a prospective, multicenter, phase 2 trial aimed at evaluating the clinical activity of the third-generation EGFR inhibitor osimertinib in patients with NSCLC harboring uncommon EGFR mutations. Among 42 treatment-naive patients enrolled over a 2-year period, the objective response rate (ORR) was 55% with a median progression-free survival (PFS) of 9.4 months. The median duration of response was 22.7 months. Consistent with earlier studies using osimertinib, common adverse events included diarrhea (47.5%), acneiform eruption/rash (42.5%), thrombocytopenia (65%), and mucositis (32.5%), but only 3 patients (7.5%) required dose reductions.

The UNICORN study3 raises several important questions. First, what is the role of osimertinib in NSCLCs with uncommon EGFR mutations moving forward? Currently, the only approved therapy for this subgroup of patients is the second-generation EGFR inhibitor afatinib. The US Food and Drug Administration and European Medicines Agency approval of afatinib was based on a post hoc analysis of patients enrolled in the LUX-Lung 2, 3, and 6 trials.2 Among 75 patients with NSCLCs harboring atypical EGFR mutations in these trials, afatinib demonstrated an ORR of 71.1% and median PFS of 11 months. Despite this activity, afatinib has been associated with high rates of skin and gastrointestinal toxicity, along with frequent need for dose reductions (28%-53%) owing to inhibition of wild-type EGFR.4 Given these concerns, there has been ongoing interest in exploring osimertinib among patients with uncommon EGFR mutations. As a third-generation EGFR inhibitor, osimertinib demonstrates relative sparing of wild-type EGFR, activity against EGFR gatekeeper resistance mutations (ie, T790M), and high central nervous system penetrance.1 Of note, uncommon EGFR mutations were generally excluded from early clinical trials of osimertinib, but several noteworthy studies have since emerged. For example, in one international, retrospective case series of 60 patients with uncommon EGFR mutations, osimertinib was associated with an ORR of 61% and median PFS of 9.5 months.5 In a separate prospective phase II study, KCSG-LU15-09, which enrolled 37 patients with atypical EGFR mutations treated with osimertinib in Korea, the ORR and median PFS were 50% and 8.2 months, respectively.6 Together with the UNICORN trial,3 these studies demonstrate consistent results and support consideration of osimertinib as an additional agent within the treatment armamentarium for patients with uncommon EGFR mutations.

A critical question moving forward is whether all uncommon EGFR mutations should be treated using the same approach. The short answer appears to be no. Among the most common atypical EGFR mutations, clinical outcomes have been heterogeneous. For example, across the KCSG-LU15-09 and UNICORN studies, patients with EGFR L861Q mutations consistently had superior clinical outcomes (ORRs, 75%-80%) while taking osimertinib, while patients with EGFR G719X and S768I mutations had more modest ORRs (45%-53% and 38%-50%, respectively).2,3,6 Such differences have prompted investigators to question historical, exon-based classifications of EGFR mutations and instead define structure-based relationships with drug sensitivity.7 Within this new paradigm, EGFR L861Q mutation is defined as classiclike alongside EGFR L858R and exon 19 deletions due to its apparent sensitivity to third-generation EGFR inhibitors like osimertinib. In contrast, both G719X and S768I map to the interior surface of the ATP-binding pocket or the C-terminal end of the αC-helix (PACC) and are termed PACC mutations.7 Because the PACC mutations alter the orientation of the P-loop and the αC-helix, affinity of EGFR binding to osimertinib may be decreased. Interestingly, afatinib does not interact with the P-loop but rather with the hydrophobic core, suggesting that this agent may have improved clinical activity against PACC mutations.7 Indeed, in Lux-Lung 2, 3, and 6, the ORRs among patients with EGFR G719X and S768I mutations treated with afatinib were 77.8% and 100%, respectively.2 Furthermore, a recent retrospective analysis demonstrated significantly longer time to treatment failure among patients with PACC mutations treated with second-generation EGFR inhibitors compared with third-generation agents.7 Collectively, these findings emphasize that atypical EGFR mutations represent a diverse and heterogenous group, and treatment of these patients using small molecules must be individualized, accounting for the molecular nature of each mutation and its functional impact on the protein and drug interaction to guide therapy.

More broadly, the UNICORN study3 highlights that for rare mutations where randomized clinical studies are not readily available, well-conducted, prospective single-arm studies may provide important insights. In addition, real-world series/registries and basket trials, such as the MATCH trial (NCT02465060), may be important vehicles to examine the activity of targeted therapies on increasingly rare molecular subgroups. Next-generation sequencing should be broadly applied to improve identification of these mutations (and other oncogenic drivers), since some EGFR alterations (eg, E709X, exon 20, and kinase domain duplications) may be missed using polymerase chain reaction alone.

Despite continued advances in the management of advanced, EGFR-mutant NSCLC, patients continue to relapse while undergoing targeted therapies. Recent strategies to augment the activity of tyrosine kinase inhibitors with novel combinations have offered glimmers of hope for improving on our existing standards. Such strategies have included combinations with chemotherapy (eg, FLAURA2 [NCT04035486]), bispecific antibodies (eg, CHRYSALIS-2 [NCT04077463]), and antibody drug conjugates (eg, EGRET [NCT05647122]). While most of these approaches are initially being explored in patients with classic EGFR mutations, such antibody-based therapeutics have the potential to inhibit a broad array of EGFR mutations, both classic and atypical, due to their ability to promote receptor internalization and target downregulation in a mutation agnostic manner.

In summary, the UNICORN study3 represents an important step forward in the management of patients with NSCLC with atypical EGFR mutations. We applaud the authors for examining this important molecular subgroup, one that has been largely overlooked in clinical trials to date. Consistent with prior reports, the UNICORN study3 demonstrates that osimertinib has promising clinical activity among patients with uncommon EGFR mutations; yet, these data also underscore that one size does not fit all. Indeed, there are subgroups within this subgroup where structure-based classifications may help to better define drug sensitivities. As we look forward toward the next decade of EGFR-mutant NSCLC research, such classifications may allow us to identify those most likely to benefit from targeted therapy, while informing which patients may require treatment intensification with emerging combinations to improve outcomes.

Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer

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Abstract

EGFR-TKI targeted therapy is one of the most effective treatments for lung cancer patients harboring EGFR activating mutations. However, inhibition response is easily attenuated by drug resistance, which is mainly due to bypass activation or downstream activation. Herein, we established osimertinib-resistant cells by stepwise dose-escalation in vitro and an osimertinib-resistant patient-derived xenograft model through persistent treatment in vivo. Phosphorylated proteomics identified that MEK1 and AKT1/2 were abnormally activated in resistant cells compared with parental cells. Likewise, EGFR inhibition by osimertinib induced activation of MEK1 and AKT1/2, which weakened osimertinib sensitivity in NSCLC cells. Consequently, this study aimed to identify a novel inhibitor which could suppress resistant cell growth by dual targeting of MEK1 and AKT1/2. Based on computational screening, we identified that costunolide could interact with MEK1 and AKT1/2. Further exploration using in vitro kinase assays validated that costunolide inhibited the kinase activity of MEK1 and AKT1/2, which restrained downstream ERK-RSK2 and GSK3β signal transduction and significantly induced cell apoptosis. Remarkably, the combination of osimertinib and costunolide showed synergistic or additive inhibitory effects on tumor growth in osimertinib-resistant cell lines and PDX model. Hence, this study highlights a potential therapeutic strategy for osimertinib-resistant patients through targeting of MEK1 and AKT1/2 by costunolide.

Background

Based on the Global Cancer Statistics of 2020, lung cancer ranks the second most frequently diagnosed cancer (11.4% of total cases) and is the leading cause of cancer-related death (18% of total cancer deaths)[1]. At present, therapeutic regimens for lung cancer include surgery, chemotherapy, immunotherapy, and targeted therapy[2]. Despite the continuous refinement of treatment options, the 5-year survival rate still remains below 20%[3]. Therefore, further investigation is needed to optimize therapeutic strategies.

Of the diverse therapeutic schemes, targeted therapy showed significant preponderance with lower side effects, stronger pertinence, and more convenience for patients[4]. Epidermal Growth Factor Receptor (EGFR)-focused targeted therapy is one of the most widely used treatments for non-small cell lung cancer (NSCLC) patients that harbor EGFR mutations, with more than 60% object response rate[5]. Osimertinib is a third generation EGFR- tyrosine kinase inhibitor (TKI) that has been approved by the FDA as a second-line treatment of EGFR acquired mutant(T790M) NSCLC patient, a first-line treatment for EGFR activating mutant (L858R or exon 19 deletion) NSCLC patients, and as a postoperative adjuvant therapy approved by National Medical Products Administration in China[6]. However, drug resistance is an inevitable issue. Due to tumor heterogeneity, mechanisms of drug resistance vary among different populations and are mainly caused by acquired EGFR mutations, activation or tetraploidization of bypass signal molecules, or phenotypic transformation[5]. Bypass activation, such as Erb-B2 receptor tyrosine kinase 2 (HER2) activation could abnormally activate the mitogen-activated protein kinase (MAPK) or protein-serine-threonine kinase- glycogen synthase kinase 3 beta (AKT-GSK3β) pathways, leading to increased cell proliferation and drug resistance[7]. Currently, EGFR-TKI combined with other drugs are popular regimens for managing drug resistance.

To further explore strategies that could overcome osimertinib resistance, we established osimertinib-resistant cells through a stepwise dose-escalation method and performed phosphorylated proteomics analysis to identify the aberrant activated pathways in resistant cells. In the present study, we identified that mitogen-activated protein kinase kinase 1 (MEK1) and AKT1/2 were abnormally activated in resistant cells. Knockdown of MEK1 and AKT1/2 inhibited the growth of osimertinib-resistant cells and partially restored osimertinib sensitivity. Moreover, we found that costunolide functions as a dual inhibitor of MEK1 and AKT1/2 that significantly induces cell apoptosis in the osimertinib-resistant cell pool. Combination of costunolide with osimertinib showed synergistic or additive inhibitory effect on osimertinib-resistant cells and a resistant patient-derived xenograft (PDX) model. These data demonstrated that costunolide may be considered as a promising strategy for osimertinib-resistant patients with activated MEK1 and AKT1/2.

Discussion

EGFR targeted therapy has achieved prominent performance for NSCLC treatment; however, acquired drug resistance inevitably limits long-term effects[7]. An appropriate drug resistant model is rather important for preclinical studies. Consequently, we generated osmertinib-resistance in cell lines harboring EFGR mutations through a step-wise dose escalation method, which showed a remarkably higher IC50 of osimertinib compared with parental cells. The lower drug susceptibility was further confirmed by foci formation and cell apoptosis assays in the resistant cells. To establish a more comprehensive resistance mechanism in vivo, we also generated an osimertinib-resistant PDX model through continuous induction using lung cancer tissue harboring an EGFR mutation. These long-term inducted resistant models are effective tools to realistically simulate the process of drug resistance in a laboratory setting.

Due to tumor heterogeneity, the reported mechanisms of osimertinib resistance may vary depending on the terms of different regimens. Acquired EGFR mutation, c-MET amplification, HER2 amplification or mutation, PIK3CA mutation, BRAF and KRAS mutation have been reported as the dominant factors contributing to osimertinib resistance in response to first-line treatment. Acquired EGFR mutation, c-MET amplification, cell cycle gene alteration, HER2 amplification, PIK3CA amplification or mutation have been reported as contributors to osimertinib resistance in response to second-line treatment. Obviously, most of the dysregulated proteins highlighted above can activate PI3K/AKT and MAPK-ERK pathways. As reported, AKT is a key modulator in regulating multi-drug resistance[12]. One mechanism occurs through AKT-triggered activation of NFκB, which can inhibit cell apoptosis and promote tumor growth. Furthermore, activated AKT also modulates cell proliferation through the phosphorylation of GSK3β, which can facilitate resistance by promoting the evasion of EGFR-targeted therapy. Besides, MEK also plays a profound role in regulating drug resistance. The paradoxical activation of MEK stimulates ERK to promote cell proliferation and drug resistance[13]. Most often, activation of MEK or AKT also play crucial roles during the drug resistance process. As reported, combination of gefitinib with MEK1/2 inhibitor synergistically inhibited gefitinib-resistant NSCLC cell growth[14]. Dual blockade of PI3K/AKT and MEK/ERK pathways potentiated gefitinib sensitivity in gefitinib resistant NSCLC and breast cancer cells. Accordingly, AKT/GSK and MEK/ERK are the most frequently dysregulated signaling pathways in acquired drug resistance. However, individually targeting AKT or MEK may facilitate active bypass or downstream signaling which will limit the success of therapies. Thus, the rational to inhibit PI3K/AKT and MAPK pathways simultaneously seems logical to produce a more robust inhibitory response that may prevent further resistance. In present study, we identified that costunolide is an effective inhibitor capable of suppressing the kinase activity of MEK1 and AKT1/2, thereby inducing significant cell apoptosis and inhibition of cell growth. Costunolide is a natural bioactive sesquiterpene lactone with antioxidant, anti-inflammatory and anticancer effects that is extracted from the roots of Saussurea lappa. Recent studies have shown that costunolide can inhibit the proliferation of various cancer cells. In ovarian cancer cells, costunolide promotes the expression of apoptosis signals, such as caspase 3, caspase 8 and caspase 9 by enhancing the production of ROS, thereby inhibiting the growth of cisplatin-resistant cells[15]. In addition, costunolide can inhibit the growth of colorectal cancer and melanoma cells by inhibiting the kinase activity of AKT[10]. Costunolide also showed a similar inhibitory effect compared with the combination of AKTi and MEKi, but at a higher dose. Our data suggested that, costunolide could act as a safe and effective inhibitor to suppress osimertinib-resistant cell growth.

Another critical finding of our study is that costunolide reversed osimertinib resistance in vivo. Due to the stable biological characteristics of patient derived tissues, we used an EGFR mutant PDX model to further evaluate the combination effects of costunolide and osimertinib. Based on the data, costunolide inhibited tumor growth and a significant synergistic effect was observed in the model. Moreover, downstream signaling effectors of MEK and AKT were markedly inhibited in the combination treatment group. Additionally, we did not observe obvious changes in total body weight, ALT or AST level between the different groups, indicating a well-tolerated dose of costunolide plus osimertinib. However, it should be noted that costunolide did not show a growth inhibitory effect in the HLG57-DMSO model. This observation is mainly because p-MEK and p-AKT protein expression levels are lower in the HLG57 relative to other lung tumor tissues. Based on this in vivo study, we concluded that the efficiency of costunolide is dependent on the levels of activated MEK1 and AKT1/2. Additional studies are required to further characterize suitable strategies for managing osimertinib-resistant cell populations deficient in active MEK and AKT.

Conclusion

Our study demonstrated that MEK1 and AKT1/2 are critical for the development of osimertinib resistance. Moreover, costunolide reversed osimertinib resistance through direct targeting of MEK1 and AKT1/2. A synergistic or additive effect was observed with the combination treatment of costunolide and osimertinb both in vitro and in vivo, which might offer a candidate strategy in the clinic.

Abbreviations

EGFR:

epidermal growth factor receptorNSCLC:

non-small cell lung cancerTKI:

tyrosine kinase inhibitorHER2:

Erb-B2 receptor tyrosine kinase 2BRAF:

B-Raf Proto-OncogenePIK3CA:

phosphatidylinositol-4,5-Bisphosphate 3-kinase catalytic subunit alphaAKT:

protein-serine-threonine kinaseGSK3β:

glycogen synthase kinase 3 betaMEK1:

mitogen-activated protein kinase kinase 1PDX:

patient-derived xenograft

source: Molecular Cancer

Herb Can Help Avoid Drug Resistance in Treating Lung Cancer: New Study

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Lung cancer ranks as the No.1 killer of all cancers globally. (Kateryna Kon/Shutterstock)

Lung cancer ranks as the No.1 killer of all cancers globally.

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Lung cancer ranks as the No.1 killer of all cancers globally. The main treatment method of Western medicine for non-small cell lung cancer, the most common type of lung cancer, is targeted therapy.

However, a thorny problem with targeted therapy is the development of drug resistance in patients.

Lee Mi-hyun, a pre-Korean medicine professor at Dongshin University in South Korea, announced on Nov. 14 that the extract of a herb “costustoot” could solve the problem of patients’ resistance to the targeted drug Osimertinib.

Lung cancer can be pathologically divided into small lung cancer and non-small cell lung cancer (NSCLC). More than 80 percent of lung cancer patients have non-small cell lung cancer, and about 50 percent of non-small cell lung cancers have mutations in the epidermal growth factor receptor (EGFR).

In treating the gene mutation, if the patient is injected with the targeted anti-cancer agent Osimertinib for a long period of time, the body will develop resistance to the drug, reducing the effectiveness of the treatment.

Osimertinib is a third-generation epidermal growth factor receptor inhibitor (EGFR-tyrosine kinase inhibitors, EGFR-TKIs), a targeted drug.

It was approved by the Food and Drug Administration and the European Union in 2017 for the treatment of non-small cell lung cancer and by the China Food and Drug Administration in 2018 for the treatment of advanced or metastatic non-small cell lung cancer.

Epoch Times Photo
A study shows that the extract of the herb “costustoot” could solve the problem of patients’ resistance to the targeted drug Osimertinib.

Lee found that this resistance is due to the over presence of MEK and AKT proteins that affect cancer cell proliferation and survival.

Based on this, Lee confirmed that costunolide, extracted from the roots of costustoot, was able to target MEK and AKT proteins, effectively blocking cancer appreciation and inducing death in oxitinib-resistant cells and animal models.

From the perspective of Korean medicine (traditional Chinese medicine), costustoot is mainly used to treat thoracic or epigastric abdominal distension, jaundice, lack of appetite, diarrhea, tenesmus, and food stagnation.

Modern pharmacological studies have shown that costustoot has the functions of protecting gastric mucosa, anti-inflammatory, analgesic, regulating gastrointestinal motility, improving gallbladder, inhibiting pathogenic microorganisms, and anti-tumor.

“We are conducting various studies to solve the problem of drug resistance in the treatment of lung cancer by Western medicine, and we will try to make these studies an opportunity for the development of Korean medicine,” Lee said.