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Molecular Biology of Lung Cancer as the Basis for Targeted Therapy
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Oliver Gautschi, Philip C. Mack, Jim Heighway, Paul H. Gumerlock, David R. Gandara
Proto-oncogenes that have been associated with lung cancer include MYC, KRAS, epidermal growth factor receptor (EGFR), HER2, and cyclin D1 (CCND1) (Table 1) (7). The MYC oncogene was isolated in the early 1980s from a retrovirus causing myelocytomatosis and carcinoma in chickens. Human MYC family genes were subsequently found to be activated in Burkitt lymphoma (MYC, translocation), neuroblastoma (MYCN, amplification), and lung cancer (MYCL, amplification). Amplification of MYC family proto-oncogenes is found in almost all small-cell lung cancers (SCLC) and is reported to confer an aggressive, resistant phenotype (9). MYC genes encode transcription factors, which dimerize with the cofactor Max and induce transcription of genes involved in cell cycle progression. MYC/Max dimers can also repress the transcription of genes that lead to cell cycle arrest following DNA damage such as cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A). Several strategies are being pursued to target MYC in cancer. Small molecule inhibitors of MYC/Max dimerization have been shown to repress MYC-induced transformation in vivo and serve as lead compounds for cancer drug development (10).
Molecular genetics of lung cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Frederic J. Kaye, Akihito Kubo
Early cytogenetic studies on SCLC cell lines showed homogeneously staining regions and double minute chromosomal fragments that were subsequently shown to represent regions of DNA amplification of the MYC, MYCN, and MYCL oncogenes (Kaye et al., 1988; Little et al., 1983; Nau et al., 1985, 1986). While approximately 25–30% of SCLC cell lines showed amplification of one member of the MYC family, co-amplification of different MYC-related genes in the same cell line was rarely observed. In addition, the incidence of MYC amplification in primary tumor samples was lower (5–18%) suggesting that this occurred as a late event (Richardson and Johnson, 1993; Wong et al., 1986). Since amplification of MYCN is associated with a worse prognosis in pediatric neuroblastoma (Brodeur et al., 1984), several studies have also reported a small decrease in survival in lung tumors with DNA amplification of MyYC but not with MYCN or MYCL (Brennan et al., 1991). The molecular consequences of Myc gene deregulation in lung cancer, however, is poorly understood. Although, activating missense mutations within the N-terminal transactivation domain of MYC have been observed in several Burkitts lymphoma samples (Bhatia et al., 1993), similar structural mutations have not been reported for lung cancer. Instead, an intrachromosomal rearrangement fusing MYCL with the adjacent RLF gene was observed in six independent SCLC samples with MYCL amplification (Kim et al., 1998; Makela et al., 1991). In addition, an anti-sense MYCL gene was fused with a novel cyclophilin-like gene in one SCLC sample (Kim et al., 1998). The role of these chimeric mRNAs in the development or progression of these lung tumors is still unknown, however, RLF has been shown to be a zinc binding protein that can affect embryonal development in rodents when fused to MYCL (MacLean-Hunter et al., 1994; Makela et al., 1995).
Synthetic lethality on drug discovery: an update on cancer therapy
Published in Expert Opinion on Drug Discovery, 2020
M. Shahar Yar, Kashif Haider, Vivek Gohel, Nasir Ali Siddiqui, Ahmed Kamal
Another set of remarkable but abstract targets are the MYC family of transcription factors. MYC, MYCL, and MYCN are often amended, overexpressed, and translocated in a number of tumors and they possess a critical role in metabolism and proliferation in numerous types of human cancers. Through the use of genomic perturbations, it was detected that the inactivation of MYC results in the induction of loss of proliferation, differentiation, or even cell mortality via apoptosis [51,52]. Once more, due to the failure of prompt inhibition of MYC via small molecules, it is now more substantial to identify synthetic lethal (synlet) interactions with MYC. Wang et al. (53) determined that agonists of the path death receptor DR5 incited programmed cell death in cells overexpress the MYC cancer gene, each in vitro and in vivo (as tumors xenografts) [54].
Pre-clinical models of small cell lung cancer and the validation of therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Jane S. Y. Sui, Petra Martin, Steven G. Gray
Of the several recurrent genetic aberrations identified in SCLC, the MYC family genes (MYC, MYCL, and MYCN) have emerged as oncogenic drivers that may constitute novel therapeutically tractable targets [104]. Using the pre-clinical models discussed above various studies have identified that alterations to the MYC family may render SCLC sensitive to either Aurora Kinase inhibitors [104,105], or to BET inhibitors [106–110] (Figure 1, Table 3). Subgroup analysis of c-MYC by IHC in archival tumor biopsies from a Phase II trial (NCT02038647) of the Aurora Kinase inhibitor Alisertib ± paclitaxel in SCLC suggests that tumors with high c-MYC expression may indeed be susceptible to this compound [111], but caution is indicated as the number of samples in this subgroup analysis was restricted to n = 33 and further studies are therefore warranted) (Table 3). In a more recent development, a Crispr-based approach in SCLC cell lines and xenografts has identified that loss of pRb in SCLC renders them hyperdependent on Aurora B kinase, and as such amenable to Aurora B kinase-specific inhibitors [112]. In the same issue, Buchanan and colleagues identified a synthetic lethal interaction with RB1 and Aurora Kinase A [113]. Identifying which patients will respond to Aurora Kinase inhibitors is therefore becoming increasingly important. In this regard, a proteomic-based approach of SCLC identified two major subgroups characterized as either high TTF-1/low cMYC, or low TTF-1/high cMYC. This low TTF-1/high cMYC subgroup was confirmed as being predictive of responsiveness to Aurora Kinase inhibitors [114] (Table 3).
MYC, MYCL, and MYCN as therapeutic targets in lung cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Daniel Massó-Vallés, Marie-Eve Beaulieu, Laura Soucek
MYCL was initially cloned from SCLC DNA, where it was found to be amplified 10-20-fold in four SCLC cell lines, as well as in one SCLC patient tumor sample [55]. The MYCL gene is located on chromosome 1 (1p32) [55]. It is subject to an EcoRI restriction site polymorphism that gives rise to a long (L) and a short (S) isoforms [56,57]; interestingly, the short isoform lacks the HLH domain, precluding it to efficiently bind DNA [58].