Targeting oncogenic drivers in lung cancer: Recent progress, current challenges and future opportunities
Introduction
Since the groundbreaking work in the early 2000's that linked specific mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene to exceptional responses to EGFR tyrosine kinase inhibitors, personalized therapeutic approaches have dramatically changed the management of advanced non-small cell lung cancer (NSCLC). This initial discovery inspired subsequent efforts to identify other actionable subsets ultimately leading to FDA approval of drugs targeting four unique molecular drivers –EGFR, anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and proto-oncogene B-Raf (BRAF)—and development of investigational drugs with promising anti-tumor activity against other oncogenes (Table 1). For several of these targets (e.g., EGFR and ALK), large phase 3 studies have shown that upfront treatment with targeted therapy induces more profound responses and improves survival relative to chemotherapy. Although similar studies have not been conducted for rarer molecular subsets, phase 2 studies have reported equally durable responses suggesting that targeted therapies should be prioritized when available. The remarkable success of personalized treatments in NSCLC is also attributable to the molecular advances that enabled identification of sensitizing alterations and the robust translational studies that have uncovered the molecular mechanisms that drive resistance to treatment. Indeed, the simultaneous study of sensitivity and resistance has propelled rapid development of potent and highly-effective next-generation inhibitors. With sequential use of increasingly potent targeted therapies, patients with NSCLC now live up to 3-4 years compared to 1 year for those without targetable mutations. However, despite these remarkable gains, targeted therapies rarely produce cures and nearly all patients with NSCLC will eventually succumb to their disease.
The effectiveness of targeted therapies is rooted in the biological phenomenon of “oncogene addiction” (Weinstein, 2002). Despite multiple genetic and epigenetic alterations within cancer cells, these cancers harbor one dominant oncogenic driver that is critical for tumor initiation and maintenance of the malignant phenotype. This notion has been supported by functional studies using transgenic mouse models with single driver oncogenes (Li et al., 2007; Politi et al., 2006; Soda et al., 2008) and by more recent genomic studies demonstrating early clonal emergence of these driver mutations (e.g. EGFR, MET, BRAF) in lung cancer evolution in the clinic (Jamal-Hanjani et al., 2017). There are three main types of genomic alterations that lead to activation of driver oncogenes; activating mutations (e.g. EGFR, BRAF), gene amplifications (e.g. MET, HER2) and gene fusions (e.g. ALK, ROS1). These result in constitutive activation of downstream growth and survival signaling pathways (e.g. MAPK, PI3K) that are normally tightly controlled in normal cells (Fig. 1). Cancers become “addicted” to these hyperactivated signaling pathways, thus inhibition of the single driver is sufficient to suppress tumor growth and induce apoptosis, the latter being a critical feature of effective targeted therapies (Faber et al., 2011). Indeed, the clinical success of targeted therapies has been the ultimate confirmation of this concept (Weinstein & Joe, 2008).
The past decade of experience with targeted therapies has also been a humbling reminder of the ability of NSCLC to adapt under therapeutic selective pressure. The insights gained have inspired a new wave of therapeutic approaches that seek to extinguish resistance in its infancy through early introduction of the most potent therapies and investigation of combinatorial strategies. In this review, we summarize the current treatment strategies for targetable drivers in NSCLC, discuss the mechanisms that mediate acquired resistance to these drugs, and preview emerging data that is driving a paradigm shift of how targeted therapies are being deployed in the clinic.
Section snippets
EGFR
Although EGFR tyrosine kinase inhibitors (TKIs) are now exclusively used for patients with NSCLCs that harbor sensitizing EGFR mutations, these drugs were initially developed for an unselected patient population based on the observation that a significant proportion of NSCLCs expressed EGFR (Fukuoka et al., 2003; Herbst et al., 2002). In early studies that explored EGFR TKIs unselected NSCLC patients, the overall activity of these drugs was largely disappointing (Gatzemeier et al., 2007;
EGFR/HER2 exon 20 insertion
EGFR exon 20 insertion mutations are the third most common type of EGFR mutation encountered in NSCLC. These mutations are present in 4-9% of EGFR-mutant NSCLCs and confer intrinsic resistance to gefitinib and erlotinib (Yasuda et al., 2013; Yasuda, Kobayashi, & Costa, 2012). Osimertinib’s activity against exon 20 insertions is being explored in ongoing clinical trials. Interestingly, poziotinib, a drug that was initially being developed for the more common EGFR mutations and is capable of
ALK
Anaplastic lymphoma kinase (ALK) rearrangements are seen in approximately 5% of NSCLCs (Kris et al., 2014; Sholl et al., 2015). In 95% of ALK-rearranged NSCLCs, ALK is fused to EML4 through a translocation involving chromosome 2 (Lin, Zhu, et al., 2018). The promoter and oligomerization domain of EML4 mediate aberrant expression and ligand-independent activation of ALK (Soda et al., 2007). In 2011, the FDA approved the first-generation ALK TKI, crizotinib for treatment of chemotherapy-resistant
ROS1
ROS1 rearrangements are identified in 1% to 2% of NSCLC patients (Bergethon et al., 2012; Rikova et al., 2007). The most frequent fusion partner is CD74 (40-45%), but a larger number of fusion partners have been identified in ROS1-rearranged NSCLC than ALK-rearranged NSCLC (Lin & Shaw, 2017). Crizotinib, a multitargeted TKI that potently targets ROS1, is the only FDA-approved therapy for treatment of ROS1-rearranged NSCLC. Approval was based on an expansion cohort of the PROFILE 1001 phase 1
BRAF
BRAF alterations are present in approximately 2-4% of NSCLCs, with one-half being the classic V600E mutation and the other half being non-V600E mutations (Kris et al., 2014; Paik et al., 2011; Sholl et al., 2015). Experience with BRAF-mutant melanoma has heavily influenced management of BRAF-mutant NSCLC. Approximately 40 to 60% of melanomas harbor BRAF mutations, and 90% of these mutations are V600E (Davies et al., 2002; Hauschild et al., 2012). Dabrafenib was developed to selectively target
RET
RET-rearrangements are seen in 1% to 2% of NSCLCs (Kohno et al., 2012; Lipson et al., 2012). The most frequent fusion partner is KIF5B (72%) (Gautschi et al., 2017). At this time, no drugs have been approved for RET-rearranged NSLCLs. However, several multi-targeted RET inhibitors (cabozantinib, lenvatinib, and vandetanib) have been approved for medullary thyroid cancer, which commonly harbors activating RET point mutations (Mulligan, 2014). In phase 2 clinical studies, cabozatinib and
TRK
The tropomyosin-related kinase (TRK) proteins TrkA, TrkB and TrkC are receptor tyrosine kinases encoded by NTRK1, NTRK2 and NTRK3. Oncogenic TRK fusions occur in a variety of tumor types—including virtually all mammary secretory analogue salivary gland carcinomas—but are quite rare in lung cancer (Vaishnavi, Le, & Doebele, 2015). Indeed, one study which screened 1378 NSCLCs only identified NTRK rearrangements in 0.1% of cases (Farago et al., 2015). To date, two studies have reported results
MET exon 14 skipping
Somatic mutations in splice sites of exon 14 promote RNA-splicing-based skipping of MET exon 14, which increases MET stability by allowing the protein to escape from ubiquitin-mediated degradation. Genetic alterations leading to MET exon 14 skipping occur in approximately 2-3% of NSCLC and are particularly enriched in tumors with adenosquamous or sarcomatoid histology (Schrock et al., 2016). MET skipping alterations predict for sensitivity to MET-directed drugs. For example, ten (66%) of the
KRAS
Even though KRAS activating mutations were initially described in lung cancer cell lines 35 years ago (Shimizu et al., 1983) and 25-30% of NSCLC harbor KRAS mutations, KRAS remains an elusive target. In most of NSCLC cases, mutations occurred in exon 2; G12C (39%), G12D (17%), or G12V (21%) (Yu et al., 2015). Given that KRAS is farnesylated to translocate to the cell membrane and become active, farnesyl transferase inhibitors have been investigated for treatment of this disease. Although
Immunotherapy and targeted therapies
The development of immunotherapies targeting the programmed cell death 1 protein (PD-1) and the programmed cell death ligand 1 (PD-L1) has a major impact on the treatment of NSCLC. Phase 3 trials comparing single-agent immunotherapies with docetaxel initially established two anti-PD-1 antibodies (nivolumab and pembrolizumab) and an anti-PD-L1 antibody (atezolizumab) as second-line therapy of advanced NSCLC (Borghaei et al., 2015; Herbst et al., 2016; Rittmeyer, et al., 2017). Both tumor cell
Up-front treatment with next-generation drugs
As discussed above, the third-generation EGFR inhibitor osimertinib, which was initially developed for T790M-mediated resistance, has now been approved for up-front use for EGFR-mutant NSCLCs. The longer PFS compared to first-generation EGFR inhibitors is likely the result of several factors including suppression of potential resistance by T790M mutant clones, increased CNS penetration, and increased selectivity for the activating mutant over wild-type EGFR allowing improved drug dosing while
Conclusion and perspectives
In this review, we have discussed the current landscape of targetable mutations in NSCLC with a focus on currently approved therapies. While the spectrum of clinically targetable mutations has expanded with the development of new inhibitors, there are no effective targeted therapies for more than a half of NSCLCs including those with KRAS mutations. In addition, even for those with effective therapies, acquired resistance remains a formidable problem. Next-generation inhibitors have been
Conflict of interest statement
ANH has received research support from Novartis, Relay Therapeutics and Amgen. IDJ has received consulting fees from Boehringer-Ingelheim and honoraria from Foundation Medicine. The remaining authors have no financial interests to declare.
Funding sources
This work was supported by Be a Piece of the Solution, by the Evan Spirito Foundation, and by the Targeting a Cure for Lung Cancer Research Fund at MGH.
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