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[SCItalk] Inhibitor of Differentiation 1 Targeting in the Treatment of Lung Cancer

Ignacio Gil-Bazo
Universidad de Navarra, Spain


Lung cancer remains the most common cancer worldwide, both in terms of incidence and mortality. In fact, lung cancer is the leading cause of cancer-related death and it is estimated that the number of deaths will increase to more than 3.1 million in 2040. Non-small cell lung cancer (NSCLC) comprises about 85% of all lung cancer cases and it is currently defined by pathological characteristics. The most common subtypes of NSCLC are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). LUAD represents the dominant histological subtype of all lung cancers, accounting for more than 40% of all diagnosed cases. The introduction of next generation sequencing (NGS), has allowed a systematic and comprehensive exploration of the genetic and epigenetic basis of this tumor. Lung cancer is one of the malignancies in which a larger number of genetic alterations, including both somatic mutations and genomic rearrangements, have been discovered. KRAS is the most common altered oncogene acting as tumor genomic driver in approximately 25%-30% of LUAD patients subtype. Patients harboring KRAS mutations have a shorter median survival compared to patients in which a driver gene alteration is present and receive targeted therapies accordingly (2.41 years vs. 3.5-4.5 years). Although the KRAS-RAF-MAPK (mitogen-activated protein kinase) pathway is downstream EGFR signaling, tumors showing mutations in KRAS, in general, are not sensitive to EGFR TKIs. To date, several approaches have been attempted to target KRAS-mutant cancers, from preventing the binding of KRAS to the cell membrane, directly inhibiting KRAS, blocking upstream activators of KRAS or canonical KRAS effector pathways, to inhibition of tumor-specific vulnerabilities or synthetic lethal interactions. Most of these inhibitory strategies have had little or no success as new therapeutic strategies for the treatment of KRAS-mutated NSCLC in the clinic for a variety of reasons.  Inhibitor of differentiation (Id) proteins belong to the basic helix-loop-helix (bHLH) family of transcription factors. There are four known members of the Id family in mammals (Id1-4). These transcription factors consist of a basic domain (E box) capable of binding to a specific DNA sequence and the domain HLH that allows the formation of dimers with other proteins. Id proteins lack the DNA binding domain, so they act as dominant-negative regulators of transcription. Elevated levels of Id proteins have been reported in several tumors and are usually associated with disease severity and poor prognosis. Id genes may act as oncofetal genes since they are commonly overexpressed during embryogenesis but they turn downregulated in adult healthy tissues. In fact, the re-expression of these genes often occurs during tumorigenesis in different tumor types. Id1 is a protein encoded by the Id1 gene, which is located on chromosome 20 in humans. It is a nuclear protein that is composed of 155 amino acids. The HLH domain is between amino acids 143 and 155. The expression of Id1 in patients with lung ADC was first described by our research group as an independent prognostic biomarker using a large series of more than 400 NSCLC patients, where Id1 was widely expressed. A high expression of Id1 in patients with LUAD was associated with a poor prognosis at different stages. In addition, in vitro Id1 silencing reduced the chemoradiotherapy resistance showed by patient-derived NSCLC cells, demonstrating Id1 as a new potential drug target candidate. More recently, we have provided genetic and pharmacological data for the potential treatment of mutant KRAS LUAD and detailed the molecular mechanisms underlying these interventional strategies. According to our findings, Id1 may be a critical gene for homeostasis of human KRAS mutant LUAD and a novel clinically relevant prognostic factor in this subgroup of LUAD patients. Moreover, Id1 blockade may also contribute to the immune response activation against lung cancer.




Prof. Gil-Bazo is the Chairman of the Department of Oncology at the University of Navarra, in Pamplona. In addition, he is Associate Professor of Medicine at the Department of Oncology at the University of Navarra School of Medicine and Director of the Predictive Markers of Response Laboratory of the Program in Solid Tumors at the Center for Applied Medical Research (CIMA). Prof. Gil-Bazo is a Medical Oncologist with extensive expertise in Thoracic Oncology, Translational Research in Oncology and Clinical Investigation.

Prof. Gil-Bazo graduated with a degree in Medicine from the University of Navarra, Spain in 1999. He obtained a PhD in Experimental and Clinical Oncology Research cum laude from the University of Navarra, in 2004. He was awarded the National Annual Research Fellowship by the Nacional Spanish Center for Oncology Research (CNIO) and the Best National Doctoral Thesis in Medicine Award.

From 2004 to 2006, Prof. Gil-Bazo joined the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center in New York, NY, USA, and worked under the supervision of Prof. Joan Massagué in Dr. Benezra’s Laboratory. Since 2006, Prof. Gil-Bazo has led the lung cancer clinical research program at the University of Navarra and served as principal investigator in more than 25 phase I-III clinical trials and sub-investigator in more than other 30 with a special interest in targeted therapies and immunotherapy.

Prof. Gil-Bazo is a member of the International Association for the Study of Lung Cancer (IASLC) and has served as faculty as well as a mentor for the IASLC Academy. He currently leads the Predictive Markers of Response Laboratory at the Center for Applied Medical Research (CIMA) and his research has been uninterruptedly funded since 2006 by private and public agencies. His team has pioneered the research trying to unravel the role of inhibitor of differentiation genes in lung cancer. His clinical and translational research has produced more than 90 papers published in peer-reviewed journals.


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