Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial

Arrieta, Óscar; Cruz‐Rico, Graciela; Soto‐Pérez‐de‐Celis, Enrique; Ramírez-Tirado, Laura Alejandra; Caballe-Perez, Enrique; Martínez-Hernández, Jorge-Negueb; Martinez-Alvarez, Ivan; Soca-Chafre, Giovanny; Macedo-Pérez, Eleazar Omar; Vega, Horacio Astudillo‐de la

doi:10.1007/s11523-016-0425-x

Cited by 15 publications

(11 citation statements)

References 49 publications

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“…HGF overexpression is frequently observed in 61% of patients with acquired resistance to EGFR-TKIs [ 64 ]. A high level of HGF in the serum is a poor prognostic factor in NSCLC patients treated with first- and second-generation EGFR-TKIs [ 65 , 66 , 67 ]. The HGF activates MET and induces resistance to EGFR-TKIs via the PI3K/AKT pathway [ 68 ].…”

Section: Acquired Resistancementioning

confidence: 99%

Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Nagano

Tachihara

Nishimura

2018

Cells

204

188

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Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib—a third-generation EGFR-TKI—targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial–mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs.

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Section: Acquired Resistancementioning

confidence: 99%

Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Nagano

Tachihara

Nishimura

2018

Cells

204

188

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“…HGF activates pro-survival signaling and promotes epithelial-mesenchymal transition of cancer cells, hindering the response to therapy. HGF has been shown to block the response of lung cancer cells to EGFR targeting drugs [ 22 , 23 ] and increased levels of serum HGF predict poor progression-free survival and overall survival in NSCLC patients treated with EGFR inhibitors [ 24 , 25 ]. Surprisingly, it has recently been shown that MET-amplified lung cancer cells become dependent on HGF for survival upon pharmacologic MET inhibition [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting the tumor-promoting microenvironment in MET-amplified NSCLC cells with a novel inhibitor of pro-HGF activation

et al. 2017

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Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment.The tumor microenvironment plays a major role in resistance to anticancer therapy. We demonstrated that fibroblasts block the response of MET-amplified NSCLC cells to the MET kinase inhibitor, JNJ38877605 in an HGF-dependent manner. Thus, MET-amplified NSCLC cells become addicted to HGF upon pharmacological inhibition of MET. HGF restored phosphorylation of MET, EGFR and RON, and maintained pro-survival AKT and ERK signaling in MET-inhibited cells.We developed a small molecule inhibitor of pro-HGF activation, SRI31215, which acts as a triplex inhibitor of the pro-HGF activating proteases matriptase, hepsin and HGF activator (HGFA). SRI31215 blocked crosstalk between tumor cells and fibroblasts and overcame fibroblast-mediated resistance to MET inhibition by preventing fibroblast-mediated reactivation of AKT and ERK signaling. Structurally unrelated triplex inhibitors of matriptase, hepsin and HGFA that we developed in parallel showed similar biological activity.Our data suggest that simultaneous inhibition of HGF and MET is required to overcome resistance to MET inhibitors in MET-amplified NSCLC cells. This provides a rationale for the development of novel combination therapeutic strategies for the treatment of NSCLC patients with MET amplification.

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“…Hepatocyte growth factor (HGF) was found to be increased [29–31] in the serum of patients with lung cancer and high levels of serum HGF may be associated with poor survival [32]. However, another study found decreased serum HGF levels in lung cancer patients [33].…”

Section: Introductionmentioning

confidence: 99%

Identification of serum proteins and multivariate models for diagnosis and therapeutic monitoring of lung cancer

et al. 2017

Oncotarget

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Lung cancer is one of the most prevalent cancers and has very poor treatment outcome. Biomarkers useful for screening and assessing early therapeutic response may significantly improve the therapeutic outcome but are still lacking. In this study, serum samples from 218 non-small cell lung cancer (NSCLC) patients, 34 small cell lung cancer (SCLC) patients and 171 matched healthy controls from China were analyzed for 11 proteins using the Luminex multiplex assay. Eight of the 11 proteins (OPN, SAA, CRP, CYFRA21.1, CEA, NSE, AGP and HGF) are significantly elevated in NSCLC and SCLC (p = 10−5−10−59). At the individual protein level, OPN has the best diagnostic value for NSCLC (AUC = 0.92), two acute phase proteins (SAA and CRP) have AUC near 0.83, while CEA and CYFRA21.1 also possess good AUC (0.81 and 0.77, respectively). More importantly, several three-protein combinations that contain OPN and CEA plus one of four proteins (CRP, SAA, CYFRA21.1 or NSE) have excellent diagnostic potential for NSCLC (AUC = 0.96). Four proteins (CYFRA21.1, CRP, SAA and NSE) are severely reduced and three proteins (OPN, MIF and NSE) are moderately decreased after platinum-based chemotherapy. Therapeutic response index (TRI) computed with 3–5 proteins suggests that approximately 25% of the NSCLC patients respond well to the therapy and TRI is significantly correlated with pre-treatment protein levels. Our data suggest that therapeutic response in NSCLC patients can be effectively measured but personalized biomarkers may be needed to monitor different subsets of patients.

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Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial

Cited by 15 publications

References 49 publications

Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Targeting the tumor-promoting microenvironment in MET-amplified NSCLC cells with a novel inhibitor of pro-HGF activation

Identification of serum proteins and multivariate models for diagnosis and therapeutic monitoring of lung cancer

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