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KRAS Oncogene in Non-Small Cell Lung Cancer: Clinical Perspectives

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KRAS Oncogene in Non-Small Cell Lung Cancer: Clinical Perspectives Román et al. Molecular Cancer (2018) 17:33 https://doi.org/10.1186/s12943-018-0789-x REVIEW Open Access KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target Marta Román1,2, Iosune Baraibar1,2, Inés López2, Ernest Nadal3, Christian Rolfo4, Silvestre Vicent2,5,6 and Ignacio Gil-Bazo1,2,5,6* Abstract Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients. Background a slight improvement in the survival of patients with ad- Lung cancer is the most common cancer worldwide both vanced NSCLC, reducing symptoms and improving the in terms of incidence (1.8 million new cases estimated in quality of life. In fact, the effect of the combination of dif- 2012) and mortality (1.6 million annual deaths). In fact, ferent chemotherapeutic agents with a platinum com- lung cancer is the leading cause of death by cancer [1, 2]. pound in patients with advanced disease observed no Non-small cell lung cancer (NSCLC) comprises about 80% significant differences between the different doublets of all lung cancer cases [3]. When patients are diagnosed tested [6]. Those poor results have been significantly im- in early stages of NSCLC the survival rates are relatively proved over the last decade through different therapeutic higher after surgical resection [4]. However, at the time of strategies such as the incorporation of a third antiangio- diagnosis, the majority of patients have already developed genic drug to a platinum-based doublet [7], the combin- advanced disease and the median survival barely exceeds ation of cisplatin with the antifolate drug pemetrexed [8] 18 months from diagnosis [5]. Patients with untreated and the implementation of pemetrexed maintenance metastatic NSCLC present an overall survival (OS) rate at monotherapy after tumor response or stabilization induced one year of only 10%, with a median survival of around 4 by a platinum-based doublet [9]. to 5 months. Classically, chemotherapy has demonstrated Also during the last decade, a number of genetic alter- ations have been described in NSCLC, being Kristen Rat Sarcoma viral oncogene (KRAS), Epidermal Growth Factor * Correspondence: [email protected] Receptor EGFR Anaplastic Lymphoma Kinase ALK Marta Román and Iosune Baraibar are co-shared first authorship. ( )and ( ) Silvestre Vicent and Ignacio Gil-Bazo are co-shared senior authorship. the most commonly altered oncogenes acting as tumor gen- 1Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, omic drivers [10]. The use of targeted therapies in NSCLC Spain EGFR ALK 2Program of Solid Tumors and Biomarkers, Center for Applied Medical individuals with an actionable driver, as and ,has Research, Pamplona, Spain shown high clinical efficacy in comparison with patients in Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Román et al. Molecular Cancer (2018) 17:33 Page 2 of 14 whom no molecular targets for a personalized therapy are HRAS and KRAS oncogenes were identified in human blad- identified [11]. In contrast, regarding KRAS oncogene, al- der and lung carcinoma cell lines, respectively [25, 26]. The though the KRAS-MAPK pathway is downstream of EGFR third member of the human RAS gene family, designated as signaling, KRAS-mutation driven lung cancers, which are NRAS, was described in human sarcoma cell lines in 1983 mainly adenocarcinomas, do not respond to EGFR tyrosine [27, 28]. kinase inhibitors (TKIs) [12]. Moreover, KRAS activation is Mariano Barbacid’s group first established the relation- one of the signaling pathways involved in resistance to ship between RAS genes and lung cancer in 1984. They EGFR TKIs and monoclonal antibodies. In spite of the conducted a landmark study which evidenced the pres- EGFR inhibition by TKIs, KRAS activation allows the ence of an activating mutation of KRAS oncogene in a downstream signaling mediated by EGF [13]. human lung cancer specimen that was not observed in Previous studies have reported that the occurrence normal tissue of the same patient [29]. Soon after, the of EGFR and KRAS mutations is strictly mutually prevalence of mutational KRAS activation in lung can- exclusive and each of these genetic alterations is cers, specifically in NSCLC, was demonstrated [30]. associated with specific clinical characteristics such KRAS mutations have been found to be almost an exclu- as pathological features, clinical background and sive feature of adenocarcinomas and are more frequent prognostic or predictive implications [14, 15]. Never- in Western populations. Pooled frequencies of KRAS theless, recent studies have described concomitant mutations range from 6.7% to 40.0% for ever/heavy genetic alterations such as EGFR or Echinoderm smokers and from 2.9 to 11.4 for never/light smokers microtubule-associated protein-like 4 (EML4) ALK [31]. During the following two decades, studies of RAS translocation with KRAS (EGFR/KRAS or EML4- focused on its biology and biochemical characteristics ALK/KRAS), most of them associated with an ac- both in normal and cancer cells, as well as in the signal- quired mutation after treatment that promotes drug ing cascade in which RAS is involved [32]. Nevertheless, resistance [16, 17]. Tumor heterogeneity according despite the increase in systematic studies of the RAS to which different mutations may coexist in different oncogene, no clinically applicable therapeutic inhibition tumor cells or in the same tumor cell could explain has proven to be successful for over 30 years. After mul- this phenomenon of concomitance. EML4-AKT/ tiple failed attempts to inhibit RAS either directly or in- KRAS double alteration represents the most common directly (downstream effectors and post-transcriptional concomitant genomic aberration and is associated modifications), ‘The RAS Initiative’ arose (2013), to fa- with poor prognosis and resistance to anti-ALK cilitate connections among RAS researchers to promote agents. Tumors with concomitant EGFR/KRAS muta- new ideas and technologies to bear on RAS. Even so, tion usually show the typical histologic patterns and RAS inhibition and the development of novel therapies cell characteristics of EGFR-mutated tumors and cor- remain an unmet clinical need [33–37]. relates with a better response to EGFR-TKIs therapy [10, 18, 19]. KRAS biology Effective therapies against KRAS have not been de- RAS proteins, including KRAS, are intracellular guanine veloped yet. Indeed, NSCLC adenocarcinoma patients nucleotide binding proteins (G proteins) which belong to with tumors harboring KRAS mutations, that account the family of small GTPases. G proteins are composed of a for 25% of the cases, show a shorter median survival G or catalytic domain, which binds guanine nucleotides (2.41 years) compared to patients candidates to per- and activates signaling, and a C-terminal hypervariable re- sonalized therapies [20, 21]. Despite all clinical ad- gion (HVR) that incorporates farnesyl or prenyl groups vances regarding personalized therapy, there is still a (post-transcriptional modifications). These modifications highly remarkable unmet clinical need since a very diverge in each isoform because of the sequence variability well-known and highly prevalent tumor driver muta- of the HVR and locate RAS proteins to the cell membrane, tion in NSCLC patients, such as KRAS, still remains where they perform their signaling function [38, 39]. The refractory to pharmacological inhibition. downstream signaling is regulated by two alternative states of RAS proteins: RAS-GTP (active form) and RAS-GDP Historical overview (inactive form). RAS-GTP complex activates several down- The ability of single-stranded murine sarcoma virus, stream signaling effectors such as the canonical Raf-MEK- Kirsten and Harvey, to transform normal mammalian genes
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