Use Of Epidermal Growth Factor Receptor Inhibitors Research Articles

Osimertinib in Combination with Bevacizumab for EGFR Mutated Recurrent Glioblastoma (GBM): A Case Report

Glioblastoma is the most common primary, malignant adult brain tumor with a median overall survival of 12-15 months after diagnosis. The standard of care includes maximal safe resection, chemoradiation, adjuvant chemotherapy with the DNA alkylator, temozolomide and tumor-treating fields. Given the recent advances in targeted molecular therapeutics and tissue sequencing, there is a growing opportunity for precision medicine in GBM treatment. In this case report, we present two patients who were found to have EGFR amplifications on molecular analysis and were treated with the EGFR inhibitor, osimertinib (Tagrisso), in combination with bevacizumab (Avastin) after tumor progression. One patient received osimertinib at first GBM progression, while the other patient received osimertinib after two other treatment regimens had failed. Both patients displayed radiographic stability several months after the expected median overall survival rate of 15 months post-diagnosis for GBM. This case report offers clinical vignettes in support of the use of EGFR inhibitors and bevacizumab in recurrent GBM with EGFR mutations.

ZYZ384 suppresses the growth of EGFR-mutant non-small cell lung cancer by activating JNK/MAPK signaling pathway.

The emergency of tyrosine kinase inhibitors has remarkably enhanced the clinical outcomes of cancer therapy, especially the use of EGFR inhibitors for non-small cell lung cancer (NSCLC). However, acquired resistance is inevitable after 8-12 months treatment. New agents or treatments are urgently required to resolve this problem. In this study, we identified that compound ZYZ384 can selectively inhibit the growth of gefitinib-resistant (G-R) lung cancer cells, without affecting that of normal lung epithelial cells. ZYZ384 induced G2 arrest in G-R NSCLC cells, decreasing the expression of Cyclin B1 and increasing the expression of P21. Meanwhile, ZYZ384 also induced apoptosis in NSCLC cells and correspondingly increased the expression of cleaved Caspase 3, 8, and 9 proteins. The expression of p-JNK, p-P38, and p-ERK were also increased in H1975 NSCLC cells treated with ZYZ384. Finally, we observed that the JNK inhibitor effectively reversed the pro-apoptotic effect of ZYZ384. In conclusion, ZYZ384 is a potential therapeutic agent to inhibit the growth of NSCLCs with EGFR mutations through activating JNK, which will help the development of related anticancer drugs.

The role of polymorphism of the epidermal growth factor gene in the formation of severe manifestations of skin toxicity caused by the use of EGFR inhibitors

Epidermal growth factor receptor (EGFR) inhibitors are widely used to treat various types of cancer, such as non-small cell lung cancer, head and neck cancer, breast cancer, pancreatic cancer, colorectal cancer. During treatment, class-mediated effects such as skin toxicity, interstitial lung disease, hepatotoxicity, ocular toxicity, hypomagnesemia, stomatitis, and diarrhea may occur. The role of epidermal growth factor and its receptors in the vital activity of keratinocytes is key. Dermatological undesirable effects occur in 60–90% of patients, and often persist throughout the entire period of EGFR inhibitor therapy.
 Currently, studies of biomarkers predicting the severity of skin complications of EGFR inhibitor therapy are extremely limited. Thus, it is relevant to study genetic markers reliably associated with the development of severe skin toxicity against the background of EGFR inhibitor therapy, because the EGFR signaling pathway is important for maintaining normal physiological function of the skin. The development of severe skin reactions leads to a reduction in the dose or discontinuation of EGFR inhibitors in the treatment of cancer. Recently, progress has been made in studies of the cutaneous toxicity of EGFR inhibitors.
 Here we briefly describe the mechanism of skin toxicity caused by EGFR inhibitors, current data on the relationship of gene polymorphism and severity of manifestations of undesirable dermatological phenomena.

Whole-course management of traditional Chinese medicine in the treatment of EGFRIs related skin toxicity in lung cancer: A series of clinical studies.

e21047 Background: Epidermal growth factor receptor inhibitors (EGFRIs) significantly prolong the survival of advanced lung cancer patients. Skin toxicities are the most common side effects caused by EGFRIs, which have the limited standard treatment, and seriously affect the long-term use of EGFRIs and the quality of life. Rash is the main type in the early stage of skin toxicity, and xerosis commonly complicated by pruritus usually occurs in the later stage regularly. Our team carried out a series of clinical studies, taking advantage of traditional Chinese medicine (TCM) in syndrome differentiation and treatment, to observe the efficacy and safety of TCM in the treatment of EGFRIs-related skin toxicity following in order. Methods: From September 2016 to September 2018, patients who occurred xerosis after using EGFRIs were enrolled and randomly divided into the treatment group and control group, respectively receiving Zizao Yangrong granules (ZYG) and placebo granules combined with vitamin E ointment. And then from August 2018 to September 2020, patients suffering from EGFRIs-related moderate to severe rash were enrolled and randomly divided into the treatment group and the control group, receiving Zhiyang Pingfu liquid and placebo liquid respectively, combined with minocycline and methylprednisolone for 14 days. Finally, based on the participants of the preliminary clinical trials, progression free survival (PFS) was determined by telephone follow-up every 3 months in patients with EGFRIs-related xerosis. Results: 66 patients finished the study of EGFRIs-related xerosis. The effective rates of xerosis among the treatment group and the control group were 84.8% and 69.7% (P < 0.05). The patients in the experimental group had better quality of life than that in the control group (P = 0.045). 54 patients finished the topical TCM for moderate to severe rash study, which the effective rates among the treatment group and the control group were 81.48% and 55.56% (P = 0.040). The median total dose of oral minocycline administration in the treatment group was lower than that in the control group (1000mg vs. 1400mg). In the end, 54 patients who received ZYG were successfully followed up. The median PFS in the treatment group was 41.6 months, and 40.9 months in the control group (HR = 0.85, 95%CI 0.48~1.51, P = 0.586). The median DLQI score of the 19 patients who received ZYG more than 8 weeks was 6, significantly higher than 4 before treatment (P＜0. 001). Conclusions: TCM had the great efficacy and safety in the treatment of EGFRIs related dermal toxicity, significantly improving the quality of life for patients. Long-term application of TCM will not affect the PFS of EGFRIs. The series of clinical studies suggested that the whole-course management of TCM in the treatment of EGFRIs related skin toxicity can increase the overall benefit of advanced lung cancer patients. Clinical trial information: ChiCTR1800017053 .

EGFR inhibitors: clinical aspects, risk factors and biomarkers for acneiform eruptions and other mucosal and cutaneous adverse effects

The frequency of the use of drugs that act on the epidermal growth factor receptor (EGFR) is increasing, with the consequent onset of cutaneous toxicity, specifically acneiform eruption. The authors extensively review the topic, focusing on describing how these drugs can affect the skin and its appendages, that is, the pathophysiology that encompasses the cutaneous toxicity related to the use of EGFR inhibitors. In addition, it was possible to list the risk factors that may be associated with adverse effects of these drugs. Based on this recent knowledge, the authors expect to aid in the management of patients who are more vulnerable to toxicity, reduce morbidities, and improve the quality of life of patients undergoing treatment with EGFR inhibitors. Other issues related to the toxicity of EGFR inhibitors, such as the clinical aspects of the acneiform eruption grades, and other different types of cutaneous and mucosal reactions, are also included in the article.

Effect of EGFR and ERBB2 amplifications and activating alterations on efficacy of lenvatinib in hepatocellular carcinoma.

600 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with a high mortality burden. Lenvatinib is an effective frontline tyrosine kinase inhibitor for HCC but is associated with primary and acquired resistance in most patients. Molecular mechanisms of resistance to lenvatinib remain unclear. Methods: We retrospectively analyzed 227 patients with HCC who underwent baseline ctDNA profiling as a component of routine clinical care, including 46 patients who had serial ctDNA analysis done at baseline and after progression to lenvatinib or ICI. Clinical data including demographics, treatment history, tumor responses, and survival outcomes were abstracted from the electronic medical record. Tumor response was categorized according to RECIST 1.1. A national registry of HCC that underwent ctDNA testing using Guardant360 was analyzed to determine the prevalence of EGFR/ERBB2 alterations in HCC. Results: Nearly a third of patients who progressed on lenvatinib demonstrated a gain in EGFR/ ERBB2 amplifications or activating mutations. No consistent trend in EGFR/ ERBB2 amplifications and alterations was found among ICI refractory HCC. Disease control rates (including complete response, partial response, and stable disease) were 20% in EGFR/ERBB2 altered HCC treated with lenvatinib, 62.5% in EGFR/ERBB2 wildtype HCC treated with lenvatinib (p = 0.05), and 58% in EGFR/ERBB2 altered HCC treated with ICIs (p = 0.09). PFS was also longer in EGFR/ERBB2 wildtype HCC treated with lenvatinib (5.9 months) and EGFR/ERBB2 altered HCC treated with ICIs (7.1 months) compared to EGFR/ERBB2 altered HCC treated with lenvatinib (2.2 months, p = 0.002). In a national cohort of 1739 patients with HCC, EGFR amplifications and activating mutations occurred in 6.5% and 1.5% of cases, respectively, and ERBB2 amplifications and activating mutations occurred in 1.9% and 0.7% of cases, respectively. Among EGFR/ERBB2 mutations, we identified recurrent gatekeeper mutations, including multiple A547T and T790M mutations, in 31% of patients. Conclusions: Our study substantiates EGFR/ERBB2 amplifications and mutations as putative drivers of lenvatinib resistance in patients with HCC and identifies the genetic mechanisms for EGFR pathway activation in refractory cancers. EGFR/ERBB2 alterations may thus represent predictive and pharmacodynamic markers of lenvatinib resistance. These findings lend support to the use of EGFR inhibitors combined with lenvatinib in previously untreated or lenvatinib refractory cancers.

Abstract B078: PP2A activation drives alternative EGFR activation in PDAC

Abstract Pancreatic ductal adenocarcinoma (PDAC) stands to become the 2nd most deadly cancer by 2030. Over 90% of PDAC patients have oncogenic KRAS mutations with the most prevalent being KRASG12D which have proven difficult to therapeutically target. Several studies have implicated EGFR signaling as critical for PDAC tumorigenesis in KRAS mutant tumors. Consistent with these findings, the first FDA-approved targeted therapeutic for PDAC was the EGFR inhibitor, Erlotinib. However, single agent use of Erlotinib has shown minimal efficacy in the clinic suggesting that this signaling is complex and needs further interrogation. Studies have shown the serine/threonine phosphatase, Protein Phosphatase 2A (PP2A), negatively regulates several downstream targets of EGFR and KRAS. Our previous studies using small molecule activators of PP2A demonstrate a heterogeneous response to PP2A activation, with some PDAC cell lines downregulating oncogenic signals and others maintaining the oncogenic signaling. Using pharmacological activation of PP2A, as well as overexpression and knockdown studies, we have identified a novel signaling cascade in which PP2A activation leads to increased expression and secretion of EGFR ligands and EGFR activation in a subset of PDAC cell lines. Given this unique feedback mechanism, we combined EGFR inhibitors with PP2A activation and found that the combination killed more cells than either agent alone. Together, our studies identify a novel role for PP2A in regulating EGFR signaling and support the combined use of EGFR inhibitors and PP2A activators to increase efficacy of both agents. Citation Format: Claire M. Pfeffer, Sydney J. Clifford, Elizabeth G. Hoffman, Gagan K. Mall, Garima Baral, Brittany L. Allen-Petersen. PP2A activation drives alternative EGFR activation in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B078.

3-Substituted-2,3-Dihydrothiazole as a promising scaffold to design EGFR inhibitors

The overexpression of EGFR has been recognized as the driver mechanism in the development of several human malignancies and the clinical use of EGFR inhibitors currently constitutes the standard of care for a wide range of malignancies, including colorectal cancer. However, the clinical efficacy of EGFR targeted inhibitors is limited by the development of intrinsic or acquired resistance, requiring the discovery of new compounds with different structural characteristics from those already developed. In this context, we explored the replacement of the aminoquinazoline pharmacophore of several FDA-approved EGFR inhibitors by its bioisosteric hydrazinothiazole moiety. A series of 14 new compounds were designed, synthesized, and evaluated as potential EGFR inhibitors. Compound 5i was active against 12 different cell lines in the NCI-60 cell line panel and showed an IC50 of 6.9 ± 0.013 µM against HCT-116 cells, with no significant toxicity against normal human fibroblasts (WI-38). Further studies showed that this compound showed submicromolar activity against EGFR and was able to induce tumor cell cycle arrest and cell apoptosis. Additionally, docking experiments, molecular dynamics and binding free energy calculations were performed and confirmed the potential of 2-hydrazino-2,3-dihydrothiazole derivatives as new EGFR inhibitors.

Role of SWI/SNF chromatin remodeling genes in lung cancer development.

SWI/SNF family of chromatin remodeling complexes uses the energy of ATP to change the structure of DNA, playing key roles in DNA regulation and repair. It is estimated that up to 25% of all human cancers contain alterations in SWI/SNF, although the precise molecular mechanisms for their involvement in tumor progression are largely unknown. Despite the improvements achieved in the last decades on our knowledge of lung cancer molecular biology, it remains the major cause of cancer-related deaths worldwide and it is in urgent need for new therapeutic alternatives. We and others have described recurrent alterations in different SWI/SNF genes in nearly 20% of lung cancer patients, some of them with a significant association with worse prognosis, indicating an important role of SWI/SNF in this fatal disease. These alterations might be therapeutically exploited, as it has been shown in cellular and animal models with the use of EGFR inhibitors, DNA-damaging agents and several immunotherapy approaches. Therefore, a better knowledge of the molecular mechanisms regulated by SWI/SNF alterations in lung cancer might be translated into a therapeutic improvement of this frequently lethal disease. In this review, we summarize all the evidence of SWI/SNF alterations in lung cancer, the current knowledge about the potential mechanisms involved in their tumorigenic role, as well as the results that support a potential exploitation of these alterations to improve the treatment of lung cancer patients.

Antibiotics in prevention of skin toxic reactions of epidermal growth factor receptor inhibitors (literature review)

The article is an overview and contains up-to-date information on the use of tetracycline antibiotics in the prevention of acne-like rash in patients receiving therapy with epidermal growth factor receptor inhibitors. According to studies, prevention of skin toxicity is necessary to maintain the effectiveness of the antitumor effect of EGFR inhibitors and to minimize the negative effect of adverse effects from the skin on the quality of life of patients. The use of tetracycline antibiotics in combination with topical therapy and photoprotection for the prevention of acne-like rash against the background of the use of EGFR inhibitors is a fairly safe method for long-term use. Of the antibacterial drugs for the prevention of acne-like rash, the most advisable is the appointment of doxycycline at a dose of 100 mg per day from the first day of taking EGFR inhibitors.

Abstract 1817: Epidermal growth factor receptor alters major histocompatibility complex class I expression on pancreatic cancer cells

Abstract Pancreatic cancer is one of the deadliest neoplasms, with a poor 5-year survival rate of just 10%. The ability of pancreatic cancer cells to evade the immune system hinders an anti-tumor response and contributes to the poor survival rate. In some cases, down regulation of major histocompatibility complex (MHC) class I cell-surface expression aids in immune evasion by preventing endogenous tumor antigens from being presented to cytotoxic T cells. The goal of this study is to evaluate the role epidermal growth factor receptor (EGFR) plays in the regulation of MHC class I expression by pancreatic cancer cells. Pancreatic cancer cell lines were treated with epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha) to activate EGFR or with the small molecule drug erlotinib to inhibit EGFR. Immunoprecipitation, western blot analysis, and flow cytometry were used to analyze cells' MHC class I expression post treatment. Human pancreatic cancer cell lines (BxPC-3, T3M4, S2-013, Panc-1) were found to decrease MHC class I expression after EGFR activation by EGF. However, activation of EGFR via TGF-alpha led to differential effects on MHC class I expression in a cell line-dependent manner. EGFR inhibition by erlotinib led to increased MHC class I expression by greater than 2.5-fold on both human and mouse pancreatic cancer cells. Mechanistic studies were done to evaluate the role of src homology 2 phosphatase (SHP2) in EGFR's regulation of MHC class I in pancreatic cancer cells, since in head and neck cancer cells SHP2 can be phosphorylated by activated EGFR and subsequently dephosphorylate STAT1 and reduce MHC class I expression. Following SHP2 knockdown by siRNA transfection, a slight increase in MHC class I expression was observed on pancreatic cancer cells, suggesting SHP2 has a minor down-regulatory role in MHC class I expression in these cells. EGFR was found to co-immunoprecipitate with MHC class I, indicating that EGFR might directly affect MHC class I expression by facilitating its endocytosis. However, after EGFR inhibition, no change in the MHC class I cell surface turnover rate was observed. Other potential mechanisms for EGFR regulation of MHC class I expression are currently being evaluated. Our discoveries defining a role for activated EGFR in reducing MHC class I expression and revealing that EGFR inhibitors can boost MHC class I levels on cancer cells could facilitate the adoption of new, more effective therapeutic tactics that combine the use of EGFR inhibitors with immunotherapies to augment patients' immune systems for effective targeting and killing of cancer cells. Citation Format: Shelby M. Knoche, Joyce C. Solheim. Epidermal growth factor receptor alters major histocompatibility complex class I expression on pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1817.

Epidermal Growth Factor Receptor: A Potential Therapeutic Target for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide and the major cause of renal failure among patients on hemodialysis. Numerous studies have demonstrated that transient activation of epidermal growth factor receptor (EGFR) pathway is required for promoting kidney recovery from acute injury whereas its persistent activation is involved in the progression of various chronic kidney diseases including DKD. EGFR-mediated pathogenesis of DKD is involved in hemodynamic alteration, metabolic disturbance, inflammatory response and parenchymal cellular dysfunction. Therapeutic intervention of this receptor has been available in the oncology setting. Targeting EGFR might also hold a therapeutic potential for DKD. Here we review the functional role of EGFR in the development of DKD, mechanisms involved and the perspective about use of EGFR inhibitors as a treatment for DKD.

First person profile: William Sellers, MD: Dr. Sellers has helped to shape the field of cancer genomics and, alongside his colleagues, is working toward its ultimate goal-to move from therapy to cure.

First person profile: William Sellers, MD: Dr. Sellers has helped to shape the field of cancer genomics and, alongside his colleagues, is working toward its ultimate goal-to move from therapy to cure.

Genetic Analysis of Triple‐Negative Breast Cancer Cell Lines and the Therapeutic Role of Akt/Nrf2 Crosstalk in Resistance to EGFR Inhibitors

IntroductionTriple‐Negative Breast Cancer (TNBC) is the most incurable subtype of breast cancer. Tang and Epidermal growth factor receptor (EGFR), which is a well‐known tyrosine kinase receptor, is expressed in 50% of TNBC cells. Chemotherapy with tyrosine kinase inhibitors (TKIs) has been recognized as the most important therapeutic method against TNBCs. TNBC patients showed resistance to EGFR targeted therapy. Recently, we studied the antitumor effects of berberine in MDA‐MB231 TNBC and MCF‐7 cells (1). We would like to report our unexpected results and the predicted association between different pathways and resistance to chemotherapy.Material and methodsTo explain the mechanism of resistance to lapatinib and other EGFR inhibitors, we analyzed genetic profiles of ten TNBC cell lines. We selected 35 genes from different pathways which are involved in resistance including Akt signaling, Nrf2 anti‐oxidant signaling, and TGF‐β/SMADs pathway together with PD‐L1, CD28, CD80, and CD86.ResultsWe clearly observed that MDA‐MB‐231 cells showed resistance to berberine and lapatinib as compared to MCF‐7. We tested lapatinib against Akt activation in MDA‐MB231 cells. We observed that lapatinib could strongly increase the level of Akt activation compared to untreated MDA‐MB231 cells. We then analyze the genetic profile of ten TNBC cell lines including MDA‐MB‐231. We observed that sixteen genes significantly upregulated or downregulated in TNBC cells. Nuclear factor erythroid 2‐related factor (NFE2L2; Nrf2) and DNMT1 were significantly overexpressed in all TNBC cells (Figure 1). Nrf2 is also activated by Akt through which several anti‐oxidant genes are expressed (2). Nrf2 reduces reactive oxygen species (ROS) and inhibits ROS‐dependent apoptosis (3). In addition, GSK3B was increased in TNBC cells. In contrast, EGFR reduced in the TNBC cells (except BT‐20 and MDA‐MB‐468). We suggest that a core of three proteins is involved in resistance to EGFR inhibitors. Akt, Nrf2, and GSK3B activations affected by DNMT1 and SIRT1 epigenetic regulations leading to resistance to therapy which need further evaluation (Figure 2).ConclusionBased on our preliminary finding, we suggest Akt as a crossroad for resistance to EGFR inhibitors. We now plan to study the mechanism of epigenetic regulation of Akt/Nrf2 axis much deeper, and discovering of potent drugs against DNMT1 and Akt in combination with EGFR targeted therapy seems to be more effective than the use of EGFR inhibitors alone in TNBC cells.Support or Funding InformationThis project was supported by the Southwest Medical University.Gene expression analysis of Akt signaling.Akt is significantly expressed in almost all TNBC cells. EGFR is expressed low compared with Akt and KRAS, two EGFR downstream signaling molecules. Nrf2 which activates anti‐oxidant and drug resistance genes is very high in all studied TNBC cells. DNMT1 involved in methylation of DNA is also significantly increased in TNBC cell lines. Gene expression lower than 4 TPM considered as low expression based.Figure 1Suggested mechanism of resistance to therapy promoted by Akt signaling.We compared the effects of berberine and lapatinib on the Akt activation in MDA‐MB231. We observed that berberine inhibited both EGFR and Akt, but lapatinib enhanced Akt activation showing the role of Akt in resistance to TKIs such as lapatinib. The interaction of Akt with GSK3B and Nrf2 may cause resistance to TKIs. This picture shows the possible mechanism of resistance.Figure 2

CMET-11. RESPONSE TO STEREOTACTIC RADIOSURGERY FOR MULTIPLE BRAIN METASTASES BASED ON HISTOLOGY-SPECIFIC SUBTYPE STATUS

Abstract BACKGROUND This retrospective study evaluated the relationship between histologic subtype and treatment outcomes following SRS for the treatment of multiple brain metastases (MBM). METHODS We analyzed patients with MBM, defined here as >= 3 lesions, treated with SRS at our institution. Primary histologies examined were NSCLC, breast, and melanoma. Patients were categorized according to histology-specific subtypes (NSCLC-EGFR, ALK, KRAS, PD-L1%; breast-HER2, ER, PR; melanoma-BRAF). The primary outcome was local control (defined by RANO-BM) and secondary outcomes included intracranial progression-free survival (iPFS) and overall survival (OS). RESULTS 141 patients met inclusion criteria (66 NSCLC, 61 breast, and 14 melanoma). HER2+ and BRAF V600E+ lesions had increased rates of local control following SRS (P=0.0048 and P=0.0256, respectively) compared to other breast/melanoma subtypes. EGFR mutation was not associated with increased local control with SRS (71 vs 74%), but increased iPFS (P=0.0031). On multivariable analysis, EGFR+ was independently associated with a decreased time-dependent risk of death (P=0.011). The use of progressively newer generations of EGFR-directed therapies was associated with stepwise decreasing risk of intracranial progression and death. HER2+ disease had improved iPFS and OS (P=0.0058 and P< 0.0001, respectively; it was not an independent risk factor for progression or death; however, the use of HER2-directed antibodies was associated with decreased risk of death (p=0.036). The use of tyrosine kinase inhibitors (i.e. lapatanib) was not associated with improvements, although this was a small subset. CONCLUSIONS Some histologic subtypes appear to have better control with SRS, with HER2+ breast cancer and BRAF V600E+ melanoma associated with improved outcomes – this requires further validation; a volumetric analysis is pending. This the protective effect of EGFR mutation appears to be partly related to use of EGFR inhibitors, with the use of newer-generation therapies leading to improved outcomes; although local control with SRS remains excellent regardless of the mutation.

The 4717C\u2009>\u2009G polymorphism in periplakin modulates sensitivity to EGFR inhibitors

The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted.

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for \u0394Np63\u03b1

BackgroundEpidermal growth factor receptor (EGFR) overexpression is associated with the development of head and neck cancer (HNC) and represents one of the main therapeutic targets for this disease. The use of EGFR inhibitors has limited efficacy due to their primary and acquired resistance, partially because of increased epithelial to mesenchymal transition (EMT). The HDAC inhibitor SAHA has been shown to revert EMT in different tumours, including HNC. In this study, we investigated the cooperative role of SAHA and the EGFR tyrosine kinase inhibitor gefitinib in both HPV-positive and HPV-negative HNC cell lines.MethodsA panel of 12 HPV-positive and HPV-negative HNC cell lines were screened for cell viability upon treatment with SAHA, gefitinib and the combination of the two. Epithelial/mesenchymal marker expression, as well as activation of signalling pathway, were assessed upon SAHA treatment. ΔNp63α silencing with shRNA lentiviral particles was used to determine its role in cell proliferation, migration and TGFβ pathway activation.ResultsWe found that both SAHA and gefitinib have antitumour activity in both HPV-positive and HPV-negative HNC cell lines and that their combination has a synergistic effect in inhibiting cell growth. SAHA treatment reverts EMT and inhibits the expression of the transcription factor ΔNp63α. Suppression of ΔNp63α reduces EGFR protein levels and decreases cell proliferation and TGFβ-dependent migration in both HPV-positive and HPV-negative HNC cell lines.ConclusionsOur results, by giving a clear molecular mechanism at the basis of the antitumour activity of SAHA in HNC cell lines, provide a rationale for the clinical evaluation of SAHA in combination with gefitinib in both HPV-positive and HPV-negative HNC patients. Further knowledge is key to devising additional lines of combinatorial treatment strategies for this disease.

Acneiform rash — skin toxic reaction to the use of EGFR inhibitors

Introduction.Inhibitors of the epidermal growth factor receptor cause the heavy dermatological adverse events, which can be the cause of change of the scheme of treatment. Acneiform rash is connected with specific inflammation of hair follicles, its weight depends on a dose of medicine and correlates with the best response to therapy at various options of tumors, in this regard effective correction of this side effect is of particular importance.Materials and methods. There were 32 patients with acneiform rash for observation; they have been divided into 3 groups. All patients received system antibacterial therapy: doxycycline 100 mg 2 times a day 10 days and topical medicines for external therapy, various on the action mechanism (tacrolimus, metronidazole, betamethasone valerate in a combination with fusidic acid). Acne Dermatology Index and Dermatology Life Quality Index were used for assessment. The received results were assesed on each visit of the patient, the final point of observations was in 3 months.Results.The significant regression of rash in all groups was in the 1st week when patients accepted doxycycline per os. Further the weakest response to therapy has shown cream with tacrolimus, the patients using gel with metronidazole has shown bigger effect, the fastest regress of Acne Dermatology Index and Dermatology Life Quality Index was observed in the patients used the combined cream with betamethasone and fusidic acid.Conclusions.The antibacterial therapy by doxycycline 100 mg 2 times a day per os at early stages of development of acneiform rash at the I—II severity gives the expressed effect and prevents deterioration of the .skin process. The combined therapy of acneiform rash of the I—II degree including doxycycline with topical cream containing a betamethasone valerate 0.1 % and fusidic acid 20 % renders the fastest and expressed effect in comparison with other combinations: the doxycycline and cream containing tacrolimus; the doxycycline and gel containing metronidazole.

FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy

IntroductionThere is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. MethodsWe performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line– and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti–EGFR therapy–treated adenocarcinoma. ResultsWe have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor–treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line– and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. ConclusionThese results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.

Transient Disappearance of RAS Mutant Clones in Plasma: A Counterintuitive Clinical Use of EGFR Inhibitors in RAS Mutant Metastatic Colorectal Cancer.

Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more recently reported in some patients with primary RAS mutant cancers, supporting for the first time an unexpected negative selection of RAS mutations during the clonal evolution of mCRC. To date, the extent of conversion to RAS wild type disease at the time of progression has not been clarified yet. As a proof of concept, we prospectively enrolled mCRC patients progressing under anti-VEGF based treatments. Idylla™ system was used to screen RAS mutations in plasma and the wild type status of RAS was further confirmed through IT-PGM (Ion Torrent Personal Genome Machine) sequencing. RAS was found mutant in 55% of cases, retaining the same plasma mutation as in the primary tumor at diagnosis, while it was found wild-type in 45%. Four patients testing negative for RAS mutations in plasma at the time of progression of disease (PD) were considered eligible for treatment with EGFR inhibitors and treated accordingly, achieving a clinical benefit. We here propose a hypothetical algorithm that accounts for the transient disappearance of RAS mutant clones over time, which might extend the continuum of care of mutant RAS colorectal cancer patients through the delivery of a further line of therapy.