MET Kinase Research Helps Gain Ground Against Lung Cancer
A unique MET mutation detected in lung cancer has paved the way to what may be a new paradigm in translational research to understand non-kinase domain mutations and MET kinase targeted therapy.
“We believe that MET receptor tyrosine kinase is a novel target in lung cancer,” says Patrick Ma, MD, Director of Aerodigestive Oncology Translational Research, “and is important for therapeutic intervention in human cancer.”
In 2003, the first preclinical prototype MET inhibitors were identified, and MET receptor was subsequently validated as “actionable” cancer target. Studies since that time have shown that the MET pathway is activated in many solid and hematological malignancies, including lung cancer, often associated with poor prognosis. MET can be altered through ligand or receptor overexpression, genomic amplification, MET mutations and alternative splicing.
Since that time, MET has become better understood. The natural ligand for MET is hepatocyte growth factor (HGF), also called scatter factor as it induces epithelial cell-cell repulsion (scattering). Aberrant HGF stimulation of MET in human cancer can occur by aberrant autocrine (intratumoral), paracrine (microenvironmental) or endocrine (circulatory) loop signal activation.
Upon HGF binding to the Sema domain, MET dimerizes leading to autophosphorylation of intracellular tyrosine residues. MET activation results in the recruitment and activation of downstream adaptor proteins and kinase targets resulting in a multitude of effects such as increased cell proliferation, cell cycle progression, scattering, motility, migration, invasion, survival, extracellular matrix remodeling, and changes in metabolism.
Thus, MET signaling contributes to tumor growth, scattering, motility, invasiveness, and metastasis, thereby playing important roles in mediating tumor addiction/dependence and tumor expedience.
Therapeutic intervention strategies to block and inhibit MET receptor oncogenic signaling cascade include blocking ligand-receptor interaction, preventing receptor dimerization, blocking MET kinase intrinsic activity and inhibiting specific downstream signal transducers.
Critical to embryogenic development of the placenta, liver, kidney, neurons and muscle, in vivo MET receptors trigger a unique biological response that leads to invasive growth. While found in numerous human solid and hematological malignancies, studies have shown that 72 percent of lung cancer tissue expressed MET, and 40 percent show MET receptor overexpression. Phospho-MET expression is found to be the highest in lung cancer among other common solid malignancies.
Since MET is found in abundance in stem and progenitor cells, but in lower levels in mature cells, it stands to reason that the concept of a cancer stem cell is key. In theory, MET is a potential marker of an expanding cell population that is changing yet retains stem cells properties; in prior studies, Ma and his fellow researchers have found that MET expression co-localizes at the lung bronchioalveolar duct junction where the bronchioalveolar stem cells were identified.
Studies taken together indicate that a logical path on investigation is to develop clinical studies of MET inhibitors, alone and in combination with EGFR tyrosine kinase inhibitor (TKI) in lung cancer both as primary or secondary strategies to prevent or overcome EGFR-TKI resistance.
In studies, both in vitro and in vivo, Ma and colleagues recently demonstrated that some drug-sensitive lung adenocarcinoma cells with mutant EGFR sensitizing to erlotinib (EGFR-TKI) remarkably exhibited a very early, within the first 6 to 9 days of drug exposure, “adaptive” tumor resistance to escape the EGFR-TKIs, with 100-fold more resistant phenotype, thereby implicating a model of “minimal residual disease.” Importantly, their research team also demonstrate similar early “adaptive” resistance in the H1975 cells (that harbor the erlotinib-resistant T790M EGFR mutation) against dual irreversible EGFR TKI plus MET inhibitor. Ma says that this early effect is important to note and intriguing to pursue, as it indicates that according to his studies, the role of MET in acquired EGFR-TKI resistance might be more relevant in the late stages of resistance development but not necessarily so in the early emergence of adaptive drug-resistance state.
Currently, more than a dozen MET inhibitors targeted to human cancers, including lung cancer, are at various stages of clinical trial studies, from preclinical to Phase 3 trials.
Included in this work is a global Phase 3 trial that Ma is involved in as principal investigator, that is drawing to a close. The (name of trial) is compiling strong and extensive evidence of efficacy in combining ARQ197 (MET inhibitor) and Tarceva (EGFR inhibitor), to shut down tumors.
“It’s gratifying to see all the work devoted to this area of research coming to clinical fruition. It is particular exciting to see that in two separate recent Phase 2 studies using MET inhibitors, significant prolonged time-to-new metastasis was observed, lending strong support to the notion of inhibiting MET signaling to impact tumor invasion and metastasis, which account for majority of human cancer morbidities and mortalities,” says Ma.
While the role of MET/HGF in cancer growth and invasion has been well-studied, he continues, and current work in trials is promising, MET inhibition strategies still deserve further studies.
ASCO 2012 Preview
Discussion of a randomized, phase II trial evaluating the efficacy and safety of axitinib as first-line treatment for metastatic renal cell carcinoma (Abstract #4503) is sure to interest clinicians attending the 2012 annual meeting of the American Society of Clinical Oncologists (ASCO) June 1-5 in Chicago.
So is the use of EEG to identify changes in brain activity corresponding with the physiology of chemotherapy-induced fatigue and cognitive dysfunction in early stage breast cancer (Abstract #95358).
These are two of many abstracts to be presented by Cleveland Clinic staff physicians and fellows at the yearly meeting.
“ASCO’s annual meeting is the largest and most prominent meeting for clinical oncologists in any and all specialties to present the freshest, most up-to-date, potentially practice-changing research. You can learn things that influence how you treat patients months before you read about them in a journal,” says Nathan Pennell, MD, PhD, a Taussig Cancer Center medical oncologist specializing in lung cancer.
Because most Cleveland Clinic oncologist subspecialize, their research tends to focuses on solving issues that affect their own patients. For example, Dr. Pennell participated in a multicenter, phase II study on adjuvant erlotinib in resected epidermal growth factor receptor (EGRF) mutation-positive non-small-cell lung cancer. His abstract (#7010) has been selected for poster discussion.
“So often, therapeutic improvements lengthen survival by several months. In this case, we were trying to improve the cure rate in this subpopulation of patients by giving the drug for two years after surgery. We and look forward to presenting our results,” he says.
Other Cleveland Clinic abstracts to be presented at ASCO include:
- Use of clinical history for Lynch syndrome risk assessment: an economic decision analysis (Abstract #1514)
- FIP200 and Rb1 expression in CNS metastasis from breast cancer (CNS met): potential predictors of patient outcome (Abstract #2014)
- Prior rituximab exposure among patients undergoing autologous stem cell transplantation for relapsed/refractory diffuse large B-cell lymphoma is associated with inferior outcomes in males compared with females (Abstract #8055)
- Adult low-grade gliomas: the Cleveland Clinic experience (Abstract #2076)
- Primary central nervous system lymphoma: the Cleveland Clinic experience (Abstract #2092)
- Low-grade gliomas in older patients (Abstract #2093)
- Prognostic nomogram in elderly patients with glioblastoma (Abstract #2096)
- Anaplastic oligodendroglial tumors: the Cleveland Clinic experience (Abstract #2100)
- The impact of bevacizumab on the occurrence and recurrence of intracranial brain metastases in non-small-cell lung cancer patients (Abstract #99105)
- Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients with metastatic castrate-resistant prostate cancer (Abstract #94612)
- A phase III randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone with placebo plus prednisone in metastatic, castration-resistant prostate cancer that has progressed during or following docetaxel-based therapy (Abstract #95127)
- New mechanistic insights into possible radiobiologic and pathophysiologic explanations for unexpectedly impressive outcomes data observed for hormone-refractory metastatic prostate cancer patients treated with radium 223 (Abstract #10623)
- Correlation of microbiomic profiles with disease status and MDR1 methylation in head and neck squamous cell carcinoma (Abstract #tbd)
- Ocular adnexal lymphoma outcomes for 82 patients treated at a single center (Abstract #tbd)
- A phase II study of intermittent sunitinib in previously untreated patients with metastatic renal cell carcinoma (Abstract #TPS4684)
- Post-atixinib systemic therapy in metastatic renal cell carcinoma (Abstract #94287)
Taussig Cancer Institute Clinical Trials
Taussig Cancer Institute provides world-class care to patients with cancer and is at the forefront of new and emerging clinical, translational and basic cancer research. Taussig annually enrolls over 1300 patients in over 240 clinical trials.
Please read more about our featured trials this month: