Personalized medicine for effective treatment of nonsmall - Cell lung cancer with targeted therapies

ACADEMIA JOURNAL OF BIOLOGY 2020, 42(3): 119–133 DOI: 10.15625/2615-9023/v42n3.14883 119 PERSONALIZED MEDICINE FOR EFFECTIVE TREATMENT OF NON- SMALL-CELL LUNG CANCER WITH TARGETED THERAPIES Duong Hong Quan Laboratory Center, Hanoi University of Public Health, Hanoi, Vietnam Received 10 March 2020, accepted 10 August 2020 ABSTRACT Lung cancer is the most common cause of cancer death worldwide, with most deaths having distant metastases. It has become increasingly complex to get effective treatment for lung cancer patients. While generalized medicine with traditional therapy resulted in comparatively poor response, personalized medicine has been well known to be an important strategy for effective treatment of lung cancer, with current focus on significant detection of clinical oncogenic drivers responsible for tumor initiation and maintenance and development of drug resistance. In lung cancer, especially in non-small-cell lung cancer (NSCLC), EGFR, ALK, RET, ROS1, BRAF, KRAS, NRAS, PIK3CA, DDR2, MET, ERBB2 have been reported to be key oncogenic drivers, which are targeted in the development and application of targeted therapeutic drugs. Personalized medicine based on these oncogenic drivers is highly recommended for treatment of advanced NSCLC patients. In this article, the significant application of personalized medicine based on the key oncogenic drivers for effective treatment of NSCLC with targeted therapeutic drugs is reviewed. Keywords: Personalized medicine, targeted therapy, non-small-cell lung cancer, treatment. Citation: Duong Hong Quan, 2020. Personalized medicine for effective treatment of non-small-cell lung cancer with targeted therapies. Academia Journal of Biology, 42(3): 119–133. https://doi.org/10.15625/2615-9023/v42n3.14883. Corresponding author email: dhq@huph.edu.vn ©2020 Vietnam Academy of Science and Technology (VAST) Duong Hong Quan 120 INTRODUCTION Lung cancer is the most frequently diagnosed human malignant tumor and remains the highest cancer-related cause of mortality in both sexes with approximately 2.1 million newly diagnosed cancer cases and 1.8 million cancer related-deaths each year worldwide (Bray et al., 2018). In 2018, there were 23667 newly diagnosed cases and 20710 deaths from this cancer in Vietnam. Despite significant advances made in both diagnostic and treatment approaches in recent years, the average 5 years survival rate remains at only 16% because the diagnosis is only conducted at advanced stages and consequently, patients have a very poor prognosis (Bray et al., 2015; Gridelli et al., 2015). Based on histopathological features, non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC) accounts for 85% and 15% of all patients with lung cancer, respectively (Travis et al., 2013). NSCLC is divided into subtypes, being adenocarcinoma (ADC) and squamous cell carcinoma (SCC) (Travis et al., 2013). Furthermore, ADC represents 50% of cases among all lung cancer subtypes (Travis et al., 2013). Personalized medicine, as defined by the National Cancer Institute (NCI), is a form of medicine using personal information about genes, proteins and environments for prevention, diagnosis and treatment of disease. Therefore, personalized medicine for NSCLC takes into consideration specific characteristics of each patient’s tumor to prescribe the most effective approach for treatment. Especially, there has been a major change in the empirical treatment of NSCLC from using one drug for all to a targeted therapy by using the most effective drug for each patient (Li et al., 2013; Reungwetwattana & Dy, 2013). Furthermore, most advances in treatment using targeted therapy in NSCLC occurred in ADC due to the identification of targetable mutations being more common than in SCC. In NSCLC, personalized medicine based on targetable profiles of tumor such as EGFR (EGFR mutation, 20−30%), ALK (ALK rearrangement, 1‒10%), RET (RET rearrangement, 1−2%), ROS1 (ROS1 rearrangement, 1−2%), BRAF (BRAF mutation, 2−5%), KRAS (KRAS mutations, 32%), NRAS (NRAS mutation, 2−3%), PIK3CA (PI3KCA mutation, 5−6%), DDR2 (DDR2 mutation, 4%), MET (MET exon 14 skipping, 1−3%) and ERBB2 (ERBB2 amplication, 1−3% and ERBB2 mutation, 2−4%) have been identified for effective treatment of NSCLC patients (Sharma et al., 2007; Suh et al., 2016; Rosas et al., 2019; Du et al., 2018; Bergethon et al., 2012; Lin, Shaw, 2017; Takeuchi et al., 2012; Farago, Azzoli, 2017; Guo et al., 2019; O’Leary et al., 2019; Aviel-Ronen et al., 2006; Vuong et al., 2018; Li et al., 2016). Personalized medicine has been considered and integrated as a routine best practice for NSCLC patients with advanced stage from the year 2000 (Pfister et al., 2004). Then, to better understand the significant role of personalized medicine in NSCLC, this review summarizes the current personalized medicine strategies for effective treatment of NSCLC patients. PERSONALIZED MEDICINE BASED ON TARGETABLE PROFILE OF TUMOR EGFR mutation EGFR, a transmembrane receptor protein with tyrosine kinase activity, has been well known to be involved in the pathogenesis of various types of cancer including NSCLC. Therefore, EGFR is the most attractive target for development of targeted therapy to treat cancer. The EGFR mutation, found in 20−30% of NSCLC with adenocarcinoma, showed potential for targeted therapies in clinical trials for the treatment of NSCLC (Sharma et al., 2007; Suh et al., 2016). The EGFR mutation is more prevalent in non- smokers and in the Asian population (Sharma et al., 2007; Shi et al., 2014). Exon 19 deletion, exon 19 insertion, exon 20 insertion and missense mutation are four main types of EGFR mutations (Sharma et al., 2007). Of these, two most common mutation contents of EGFR, being exon 19 deletion (delE746-A750) and exon 21 missense mutation (L858R), are found in 90% of EGFR Personalized medicine for effective treatment 121 mutations in NSCLC patients with adenocarcinoma. The second most common mutations of EGFR are frame deletion in exon 19 or point mutations in exon 18 and exon 21. The third most common mutation of EGFR is exon 20 insertion (Sharma et al., 2007). Targeted therapeutic drugs have been used for effective treatment of NSCLC patients with indicated EGFR mutation (Table 1). However, all NSCLC patients harboring EGFR mutation will eventually become resistant to Erlotinib and Gefitinib (first-generation EGFR inhibitors). Acquired resistance due to the T790M mutation in exon 20 of EGFR is detected in 50−60% of cases with secondary resistance to first-generation EGFR inhibitors (Chong & Jänne, 2013). Afatinib and Dacomitinib (second-generation EGFR inhibitors) have been developed for such cases (Li et al., 2008). However, NSCLC patients with T790M would also develop resistance to Afatinib. Osimertinib, a third-generation EGFR inhibitor developed to treat NSCLC patients previously treated with Afatinib, is now approved by FDA, and recommended for treatment of EGFR T790M positive NSCLC patients (Mok et al., 2017). ALK rearrangement and/or mutation ALK, a transmembrane tyrosine kinase receptor, was identified specifically in NSCLC (Rikova et al., 2007). Rearrangement, point mutation and amplification are three types of oncogenesis in ALK. ALK rearrangement, identified in approximately 1−10% of NSCLC patients, could benefit from targeted therapies for the treatment of NSCLC (Rosas et al., 2019; Du et al., 2018). To date, in NSCLC, 20 distinct ALK rearrangements have been detected, among which 11 are oncogenetic drivers, being EML4-ALK, KIF5B-ALK, KLC1- ALK, HIP1-ALK, BIRC6-ALK, PRKAR1A- ALK, PPM1B-ALK, EIF2AK3-ALK, BCL11A-ALK, CEBPZ-ALK and PICAM- ALK (Rosas et al., 2019; Du et al., 2018). Among these oncogenetic drivers, EML4- ALK, found in approximately 3−13% of all ALK arrangements, occurs most frequently in NSCLC (Inamura et al., 2008; Shaw et al., 2009; Sun et al., 2010; Horn & Pao, 2009; Du et al., 2018). ALK rearrangements are especially more common in younger adenocarcinoma patients who are non- smokers or light smokers (Camidge et al., 2010; Shaw et al., 2009). Targeted therapeutic drugs such as Crizotinib (first-generation inhibitor of ALK and MET), Ceritinib (second-generation inhibitor of ALK), Alectinib (inhibitor of ALK), Brigatinib (third-generation inhibitor of ALK and EGFR), and Lorlatinib (third-generation inhibitor of ALK and ROS1) have been used for the effective treatment of NSCLC patients with indicated ALK rearrangement and/or mutation (Table 1). Another main type of oncogenesis in ALK is point mutation. Acquired resistance due to secondary mutations of ALK in NSCLC patients with ALK rearrangement treated with Crizotinib, are caused by mutations in the target ALK gene (Toyokawa & Seto, 2015; Lin et al., 2017). The secondary mutations of ALK, causing acquired resistance to ALK inhibitor such as Crizotinib, are 1151Tins, L1152R, C1156Y, F1174L, L1196M, L1198F, G1202R, S1206Y, G1269A, I1171T, D1203N and V1180L (Lin et al., 2017; Du et al., 2018). To treat effectively for NSCLC patients with ALK rearrangement previously treated with Crizotinib, Alectinib and Ceritinib have been developed (Shaw et al., 2014; Shaw et al., 2016). Afterwards, NSCLC patients with ALK rearrangement also develop resistance to Alectinib and/or Ceritinib due to new mutations in ALK such as as G1202R, for which Lorlatinib has been developed (Katayama, 2017). ROS1 rearrangement Rearrangement of ROS1, a receptor of the insulin receptor family with constitutive kinase activity, were found in NSCLC in 2007 (Rikova et al., 2007). ROS1 rearrangement, identified in 1−2% of NSCLC, could benefit from targeted therapies (Bergethon et al., 2012; Lin, Shaw, 2017). To date, 14 distinct ROS1 rearrangement have been detected in NSCLC, being CD74-ROS1, SDC4-ROS1, Duong Hong Quan 122 SLC34A2-ROS1, EZR-ROS1, TPM3-ROS1, LRIG3-ROS1, FIG-ROS1, KDELR2-ROS1, CCDC6-ROS1, MSN-ROS1, TMEM106B- ROS1, TPD52L1-ROS1, CLTC-ROS1 and LIMA-ROS1 (Lin, Shaw, 2017). Among these contents of ROS1 rearrangements, CD74- ROS1 occurs most frequently in NSCLC (Gainor, Shaw, 2013). Crizotinib (inhibitor of ALK and MET) has been used for the effective treatment of NSCLC patients with indicated the ROS1 rearrangements (Table 1). RET rearrangement Rearrangement in RET, a proto-oncogene, were identified to be the result of transfection of the NIH3T3 cells with high molecular weight DNA of a human T-cell lymphoma (Takahashi et al., 1985). RET rearrangements found in 1−2% of NSCLC cases, could benefit from targeted therapies (Takeuchi et al., 2012; Farago, Azzoli, 2017). To date, the RET rearrangement detected in NSCLC are KIF5B-RET, CCDC6-RET, NCOA4-RET, EPH5-RET and PICALM-RET (Takeuchi et al., 2012; Farago, Azzoli, 2017). Among these, KIF5B-RET is the most common RET rearrangement in NSCLC (72%) (Takeuchi et al., 2012; Kohno et al., 2012; Farago, Azzoli, 2017). Targeted therapeutic drugs such as Cabozantinib (a multikinase inhibitor active against VEGFR2, MET, ROS1, AXL, KIT, TIE2 and RET), and Vandetanib (a multikinase inhibitor active against VEGFRs, EGFR, and RET) have been used for the effective treatment of NSCLC patients with indicated RET rearrangement (Table 1). BRAF mutation BRAF, an intracellular serine/threonine kinase, activates the MAPK signaling pathway to regulate cell growth and proliferation. BRAF mutations, found in 2−5% of NSCLC cases, could benefit from targeted therapies (Suh et al., 2016; Guo et al., 2019; O’Leary et al., 2019). For NSCLC, missense mutation of BRAF, classified into V600E (90%) and non- V600E (G469L and Y472C) subtypes, mainly in current and former smokers (Marchetti et al., 2011; Cardarella et al., 2013). Especially, all NSCLC patients with the non-V600E subtypes are heavy smokers (Cardarella et al., 2013). Dabrafenib and/or Vemurafenib (BRAF inhibitor) have been used for the effective treatment of these NSCLC patients with indicated BRAF mutations (Table 1). KRAS mutation KRAS, a member of the RAS family, activates the RAF/MAPK and PI3K signaling pathway to control cell growth and proliferation. KRAS mutations, found in up to 32% of NSCLC cases, could benefit from targeted therapies (Aviel-Ronen et al., 2006; Suh et al., 2016; Guo et al., 2019). In NSCLC the most common mutations of KRAS at codon 12 are G12C (43%), G12V (18%) and G12D (11%). Especially, KRAS mutation is predominantly associated with NSCLC patients who have adenocarcinoma and are non-Asian smokers (Aviel-Ronen et al., 2006). Targeted therapeutic drug such as Trametinib (MEK1/2 inhibitor) has been used for the effective treatment of NSCLC patients with indicated KRAS mutations (Table 1). Furthermore, in NSCLC, KRAS mutations are well known as non-druggable targets that predict resistance to EGFR inhibitors such as Erlotinib and Gefitinib (Chong, Jänne, 2013) and to ALK inhibitors such as Crizotinib (Gainor et al., 2013), i.e. KRAS mutations are mutually exclusive with EGFR mutations and ALK rearrangements in NSCLC (Chong, Jänne, 2013; Gainor et al., 2013). NRAS mutation NRAS, a member of RAS family and a GTPase related to KRAS, regulates cell growth, proliferation and differentiation. NRAS mutations, identified in approximately 2−3% of NSCLC case, could benefit from targeted therapies (Suh et al., 2016). NRAS mutations are more common in NSCLC patients being current/former smokers (Ohashi et al., 2013). Trametinib (MEK1/2 inhibitor) has been used for effective treatment of NSCLC patients with indicated NRAS mutations (Table 1). PI3KCA mutation PI3KCA, a catalytic subunit of the class IA PI3K which is the member of a family of Personalized medicine for effective treatment 123 heterodimeric kinases, plays an important role in the regulation of cell growth, survival and motility. PI3KCA amplification and mutation are two main types of aberrant activation of PI3K. Among them, PI3KCA mutations, found in approximately 5−6% of NSCLC patients, could benefit from targeted therapies (Suh et al., 2016; Guo et al., 2019). targeted therapeutic drugs such as Erlotinib and/or Gefitinib (EGFR inhibitor) have been used for the effective treatment of NSCLC patients with indicated PI3KCA mutation (Table 1). DDR2 mutation DDR2, a receptor tyrosine kinase binding collagen I and III as its endogenous ligand, promotes cell proliferation, migration and metastasis by regulation of EMT (Vogel et al., 1997; Labrador et al., 2001; Walsh et al., 2011). DDR2 mutations, found in approximately 4% of NSCLC cases, could benefit from targeted therapies (Suh et al., 2016; Guo et al., 2019). Only one targeted therapeutic drug, Dasatinib (SRC inhibitor), has been used for the effective treatment of NSCLC patients with indicated DDR2 mutation (Table 1). MET mutation MET, a transmembrane receptor tyrosine kinase, plays an important function in embryogenesis, tumor growth and metastasis. Amplification, activating point mutation and MET exon 14 skipping are three main types of MET gene alteration. Among them, MET exon 14 skipping, reported in approximately 1−3% of NSCLC patients, could benefit from targeted therapies (Suh et al., 2016; Vuong et al., 2018). Targeted therapeutic drugs such as Crizotinib (inhibitor of MET and ALK), Capmatinib (MET inhibitor) and/or Glesatinib (inhibitor of MET and AXL) have been used for the effective treatment of NSCLC patients with indicated mutations in MET exon 14 skipping (Table 1). ERBB2 mutation ERBB2, a member of the ERBB family, activates downstream signaling pathway to drive oncogenesis in several types of cancer including lung cancer when forming with other members of the ERBB family as EGFR (Yarden, Sliwkowski, 2001). ERBB2 amplication and mutations are found in 1−3% and 2−4% of NSCLC patients, respectively (Suh et al., 2016; Li et al., 2016). In ERBB2 aberration, exon 20 insertions could benefit from targeted therapies. Targeted therapeutic drugs such as Afatinib (EGFR inhibitor) and/or Neratinib (ERBB2 inhibitor) have been used for the effective treatment of NSCLC patients with indicated ERBB2 mutation (Table 1). Table 1. Personalized medicine with targeted therapeutic drugs for effective treatment of NSCLC patients harboring targetable profile Oncogenic drivers Types of Mutation/Rearrangement Mutations/Fusions Targeted therapy drugs EGFR Missense mutation G719A Erlotinib Gefitinib Afatinib Dacomitinib Osimertinib G719S G719C G719D S768I T790M C797S L858R L861Q L861R Exon 19 deletion mutation K745_A750delinsK K745_T751delinsKI Duong Hong Quan 124 K745_E746delinsK K745_E749delinsK K745_A750delinsKIP K745_T751delinsKIP K745_T751delinsKA K745_T751delinsK K745_T752delinsKI K745_T752delinsKV E746_A750del E746_A751del E746_T751delinsA E746_T752delinsA E746_T752delinsV E746_T752delinsD E746_A750delinsEP E746_T751delinsEQ E746_A750delinsRP E746_A750delinsQP E746_T751delinsS E746_T751delinsI E746_T751delinsIP E746_T751delinsQ E746_T751delinsL E746_S752delinsI E746_S752del E746_P753delinsLS E746_P753delinsIS E746_A750delinsAP E746_A750delinsVP E746_A751delinsVA E746_A751delinsVP E746_A751delinsV E746_P753delinsVS E746_P753delinsVQ E746_A750delinsDP E746_T751delinsEP E746_T751delinsE E746_S752delinsEQH E746_S752delinsEQ E746_P753delinsE L747_E749del L747_A750delinsP L747_T751delinsP L747_T751del L747_S752del Personalized medicine for effective treatment 125 L747_P753delinsQ L747_T751delinsS L747_S752delinsS L747_P753delinsS L747_T751delinsQ L747_T751delinsPT L747_T751delinsA L747_S752delinsQ L747_S752delinsQH L747_K754delinsANKG L747_K754del L747_A755delinsAN L747_K754delinsST L747_A755delinsSKG E749_E758delinsE E749_K754delinsE A750_E758delinsP A750_E758delinsA A750_I759delinsAN T751_I759delinsS T751_I759delinsI T751_I759delinsN T751_I759delinsREA T751_I759delinsT S752_I759del P753_I759del Exon 19 insertion mutation I744_K745insKIPVAI K745_E746insIPVAIK K745_E746insVPVAIK K745_E746insTPVAIK Exon 20 insertion mutation M766_A767insASV M766_A767insAI A767_S768insTLA S768_V769insVAS V769_D770insGVV V769_D770insGSV V769_D770insDNV V769_D770insCV V769_D770insASV D770_N771insY D770_N771insSVD D770_N771insNPH D770_N771insN D770_N771insGT D770_N771insGL Duong Hong Quan 126 D770_N771insGF D770_N771insGD D770_N771insG D770_N771insAPW N771delinsTH N771delinsSH N771delinsSGH N771_P772insRH N771_P772insN N771_P772insH P772_H773insV P772_H773insTHP P772_H773insHV H773_V774insQ H773_V774insPH H773_V774insNPH H773_V774insH H773_V774insAH V774_C775insHV ALK Rearrangement EML4-ALK Crizotinib Ceritinib Alectinib Lorlatinib KIF5B-ALK KLC1-ALK HIP1-ALK BIRC6-ALK PRKAR1A-ALK PPM1B-ALK EIF2AK3-ALK BCL11A-ALK CEBPZ-ALK PICAM-ALK Missense mutation 1151Tins L1152R C1156Y F1174L L1196M L1198F G1202R S1206Y G1269A I1171T D1203N V1180L ROS1 Rearrangement CD74-ROS1 Crizotinib SDC4-ROS1 SLC34A2-ROS1 Personalized medicine for effective treatment 127 EZR-ROS1 TPM3-ROS1 LRIG3-ROS1 FIG-ROS1 KDELR2-ROS1 CCDC6-ROS1 MSN-ROS1 TMEM106B-ROS1 TPD52L1-ROS1 CLTC-ROS1 LIMA1-ROS1 RET Rearrangement KIF5B-RET Cabozatinib Vandetanib CCDC6-RET NCOA4-RET EPHA5-RET PICALM-RET BRAF Missense mutation V600E Vemurafenib Dabrafenib G469L Y472C KRAS Missense mutation G12A Trametinib G12D G12V G12S G12R G12C G13D G13C G13R G13S G13A Q61K Q61L Q61R Q61H NRAS Missense mutation G12C Trametinib G12R G12S G12A G12D Q61K Q61L Q61R Q61H PIK3CA Missense mutation H1047R Erlotinib Duong Hong Quan 128 H1047L Gefitinib DDR2 Missense mutation S768R Dasatinib MET Exon 14 skipping mutation c.2888-18_2888-7del12 Crizotinib Capmatinib Glesatinib c.3024_3028+7del12 c.3001_3021del21 c.3028G>T c.2888delA c.3028G>A c.3028G>C c.3028+1G>T c.2888-29_2888-6del24 ERBB2 Exon 20 insertion mutation G776delinsVC Afatinib Neratinib V777_G778insCG G778_S779insG S779_P780insVGS P780_Y781insGSP G776Lfs*98 CONCLUSION AND FUTURE PERSPECTIVES Personalized medicine for effective treatment of NSCLC patients with EGFR mutations, ALK rearrangements and/or mutations, ROS1 rearrangements, RET rearrangements, BRAF mutations, KRAS mutations, NRAS mutations, PIK3CA mutations, DDR2 mutations, MET mutations and ERBB2 mutations has become the international standard of care for NSCLC patients (Fig. 1, Table 1). However, standardization and validation of detection methods for oncogenic drivers in NSCLC patients is very essential for accurate and reproducible results. Next-generation sequencing (NGS), a powerful detection method, will offer the vision of personalized medicine where an individual’s treatment can be based on that patient’s individual molecular profile, rather than on historical population-based medicine. NGS will be also the powerful method to identify new biomarkers for early diagnosis of lung cancer and is increasingly used to guide personalized treatments decisions for NSCLC patients. Figure 1. Personalized medicine with targeted therapeutic drugs for effective treatment of NSCLC patients harboring targetable profile Personalized medicine for effective treatment 129 REFERENCES Aviel-Ronen S., Blackhall F. H., Shepherd F. A., Tsao M. S., 2006. K-ras mutations in non-small-cell lung carcinoma: a review. Clin. Lung. Cancer., 8(1): 30−38. Bergethon K., Shaw A. T., Ou S. 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