cancers Review Small Cell Lung Cancer: State of the Art of the Molecular and Genetic Landscape and Novel Perspective Valeria Denninghoff 1 , Alessandro Russo 2,3 , Diego de Miguel-Pérez 2 , Umberto Malapelle 4 , Amin Benyounes 5, Allison Gittens 2, Andres Felipe Cardona 6,7,8 and Christian Rolfo 2,* 1 National Council for Scientific and Technical Research (CONICET), University of Buenos Aires, Buenos Aires C1122AAH, Argentina; [email protected] 2 Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; [email protected] (A.R.); [email protected] (D.d.M.-P.); [email protected] (A.G.) 3 Medical Oncology Unit, A.O. Papardo, 98158 Messina, Italy 4 Department of Public Health, University of Naples Federico II, 80138 Naples, Italy; [email protected] 5 Thoracic Oncology, Inova Schar Cancer Center, Fairfax, VA 22031, USA; [email protected] 6 Clinical and Translational Oncology Group, Clínica del Country, Bogotá 110221, Colombia; [email protected] 7 Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá 110111, Colombia 8 Molecular Oncology and Biology Systems Research Group (Fox-G/ONCOLGroup), Universidad el Bosque, Bogotá 110121, Colombia * Correspondence: [email protected]; Tel.: +1-(410)-328-7224 Citation: Denninghoff, V.; Russo, A.; Simple Summary: Small cell lung cancer (SCLC) continues to carry a poor prognosis with a five-year de Miguel-Pérez, D.; Malapelle, U.; survival rate of 3.5% and a 10-year survival rate of 1.8%. The pathogenesis remains unclear, and Benyounes, A.; Gittens, A.; Cardona, there are no known predictive or diagnostic biomarkers. The current SCLC classification as a single A.F.; Rolfo, C. Small Cell Lung entity hinders effective targeted therapies against this heterogeneous neoplasm. Despite dedicated Cancer: State of the Art of the decades of research and clinical trials, there has been no change in the SCLC treatment paradigm. Molecular and Genetic Landscape This review summarizes the body of literature available on SCLC’s genomic landscape to describe and Novel Perspective. Cancers 2021, SCLC’s molecular/genetic aspects, regardless of therapeutic strategy. 13, 1723. https://doi.org/10.3390/ cancers13071723 Abstract: Small cell lung cancer (SCLC) is a highly proliferative lung cancer that is not amenable to Academic Editor: Mary surgery in most cases due to the high metastatic potential. Precision medicine has not yet improved Frances McMullin patients’ survival due to the lack of actionable mutations. Intra- and intertumoral heterogeneity allow the neoplasms to adapt to various microenvironments and treatments. Further studying this Received: 4 March 2021 heterogeneous cancer might yield the discovery of actionable mutations. First-line SCLC treatment Accepted: 31 March 2021 has added immunotherapy to its armamentarium. There has been renewed interest in SCLC, and Published: 6 April 2021 numerous clinical trials are underway with novel therapeutic approaches. Understanding the molecular and genetic landscape of this heterogeneous and lethal disease will pave the way for novel Publisher’s Note: MDPI stays neutral drug development. with regard to jurisdictional claims in published maps and institutional affil- Keywords: small cell lung cancer; gene pathway; pathobiology; targeted therapy iations. 1. Small Cell Lung Cancer (SCLC) General Considerations Copyright: © 2021 by the authors. SCLC is a highly proliferative lung cancer that is not amenable to surgery in most Licensee MDPI, Basel, Switzerland. cases due to the high metastatic potential. It is considered a high-grade neuroendocrine This article is an open access article carcinoma with characterizing molecular alterations [1]. SCLC’s estimated five-year sur- distributed under the terms and vival rate is 3.5%, and the 10-year survival rate is 1.8% [2]. Smoking history is present conditions of the Creative Commons in 95% of the cases, and therefore carcinogenesis is linked to tobacco and its substrates, Attribution (CC BY) license (https:// possibly through a DNA damage mechanism; however, the exact mechanism is unknown. creativecommons.org/licenses/by/ 4.0/). Cancers 2021, 13, 1723. https://doi.org/10.3390/cancers13071723 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 1723 2 of 12 Cancers 2021, 13, x FOR PEER REVIEW 2 of 12 The genes that affect oncogenes or tumor suppressor genes are usually acquired, not inher- ited. Tumor protein p53 (TP53) and retinoblastoma 1 (RB1) are the most common tumor suppressor genes (98% and 91%, respectively) [3]. These tumors are highly proliferative, as demonstratedThe genes that byaffect Ki67 oncogenes immunohistochemistry or tumor suppressor [1,4 –genes7]. SCLC are usually is the deadliestacquired, lungnot in- cancer subtypeherited. Tumor and is uniformlyprotein p53 fatal (TP53 [8)]. and Lack retinoblastoma of early detection 1 (RB1 and) are poorthe most response common to standard tu- treatmentmor suppressor are the genes main (98% contributing and 91%, respective factors toly) a [3]. poor These outcome. tumors are SCLC highly usually prolifera- responds totive, frontline as demonstrated therapy (60%–80%by Ki67 immunohistochemi response rates);stry however, [1,4–7]. SCLC within is the 6–12 deadliest months, lung it can- becomes cer subtype and is uniformly fatal [8]. Lack of early detection and poor response to standard refractory to salvage treatments. Therefore, an understanding of resistance mechanisms treatment are the main contributing factors to a poor outcome. SCLC usually responds to is urgently needed. There has been renewed interest in SCLC, and numerous clinical frontline therapy (60%–80% response rates); however, within 6–12 months, it becomes refrac- trials are underway with novel therapeutic approaches. Understanding the molecular and tory to salvage treatments. Therefore, an understanding of resistance mechanisms is urgently geneticneeded. landscapeThere has been of thisrenewed heterogeneous interest in SCLC, and and lethal numerous disease clinical will pave trials theare underway way for novel drugwith development.novel therapeutic approaches. Understanding the molecular and genetic landscape of this heterogeneous and lethal disease will pave the way for novel drug development. 2. Molecular Pathways Involved in SCLC Development and Progression 2. MolecularThree pivotal Pathways comprehensive Involved in genomicSCLC Development analyses of and SCLC Progression shed light on SCLC develop- ment’sThree principle pivotal molecular comprehensive pathways genomic [9–11 analys]. Thees limitationof SCLC shed of these light analyseson SCLC isdevel- the small numberopment’s of principle samples, molecular most likely pathways due to [9–11]. the lack The of limitation clinical specimens, of these analyses as this is disease the is notsmall usually number treated of samples, with most surgery. likely Therefore, due to the experimentallack of clinical specimens, models and/or as this celldisease lines are fundamentalis not usually fortreated genomic with analysissurgery. Therefor and sensitivitye, experimental to treatments. models Althoughand/or cellTP53 lines andare RB1 arefundamental the most commonfor genomic mutations analysis and found sensitivity in SCLC, to thesetreatments. alterations Although cannot TP53 yet and be RB1 targeted pharmacologically.are the most common Peifer mutations et al. sequencedfound in SCLC, 29 SCLC these exomes,alterations two cannot tumor yet genomes, be targeted and 15 tumorpharmacologically. transcriptomes. Peifer They et al. observedsequenced a 29 high SCLC mutation exomes, rate two oftumor 7.4 ± genomes,1 protein-changing and 15 mutationstumor transcriptomes. per million They base pairs;observed loss a ofhigh TP53 mutation and RB1; rate mutations of 7.4 ± 1 andprotein-changing amplifications of MYCL1,mutations MYCN per million, and baseMYC pairs;; mutations loss of TP53 in the and histone-modifying RB1; mutations and genes amplifications CREBBP, of EP300, andMYCL1,MLL MYCN; mutations, and MYC in PTEN,; mutations SLIT2 ,in and theEPHA7 histone-modifying; focal amplification genes CREBBP, in FGFR1 EP300,tyrosine kinaseand MLL gene; mutations [9]. George in PTEN, et al. SLIT2 conducted, and EPHA7 whole-genome; focal amplification sequencing in FGFR1 of 110 tyrosine first frozen tumorkinase samplesgene [9]. fromGeorge patients et al. conducted with limited whol ande-genome extensive-stage sequencing small of 110 cell first lung frozen cancer tu- and theirmor samples matched from normal patients DNA with [11 limited]. They and observed extensive-stage an elevated small mutation cell lung ratecancer of 8.62and non- their matched normal DNA [11]. They observed an elevated mutation rate of 8.62 non- synonymous mutations per million base pairs (Mb). C: G->A: T transversions were seen in synonymous mutations per million base pairs (Mb). C: G->A: T transversions were seen 28% of all mutations and were linked to heavy smoking. The signaling pathways affected in 28% of all mutations and were linked to heavy smoking. The signaling pathways af- in SCLC and frequently aberrant genes in SCLC are shown in Figure1. fected in SCLC and frequently aberrant genes in SCLC are shown in Figure 1. FigureFigure 1. SignalingSignaling pathways pathways recurrent recurrent affected affected in smal inl small cell lung cell cancer lung cancer(SCLC) (SCLC)and frequently and frequently aberrant genes (created with BioRender.com, accessed on 28