Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer

Kim, Hyun‐Seok; Mendiratta, Saurabh; Kim, Jiyeon; Pecot, Chad V.; Larsen, Jill E.; Zubovych, Iryna O.; Seo, Bo Yeun; Kim, Jimi; Eskiocak, Banu; Chung, Hannah; McMillan, Elizabeth A.; Wu, Sherry Y.; Brabander, Jef K. De; Komurov, Kakajan; Toombs, Jason E.; Wei, Shuguang; Peyton, Michael; Williams, Noelle S.; Gazdar, Adi F.; Posner, Bruce A.; Brekken, Rolf A.; Sood, Anil K.; DeBerardinis, Ralph J.; Roth, Michael G.; Minna, John D.; White, Michael A.

doi:10.1016/j.cell.2013.09.041

Cited by 157 publications

(200 citation statements)

References 82 publications

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“…We subsequently analyzed NSCLC cell line models harboring a mutation in the gene encoding the inflammasome subunit NLRP3, which has previously been linked to hypersensitivity to RNAi-mediated FLIP depletion (20). In agreement with the literature, NLRP3 mutated HCC15 and H1373 cell lines were found to be highly sensitive to FLIP-depletion as determined by PARP cleavage ( Figure 3C).…”

Section: Radiation Induced Cell Death Issupporting

confidence: 83%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway.Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. KA McLaughlin et al. FLIP-mediated radio-resistance in NSCLC3

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Section: Radiation Induced Cell Death Issupporting

confidence: 83%

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

McLaughlin

Németh

Bradley

et al. 2016

Molecular Cancer Therapeutics

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“…KRAS mutant NSCLC patients with concurrent LKB1 loss had a high number of metastatic sites at the time of diagnosis, and had a high incidence of extra-thoracic metastases [159]. Interestingly, concurrent mutations in KRAS and STK11 in human cancer cells resulted in susceptibility to the depletion of the coatomer complex I subunits [160], which are required for lysosomal maturation and CDC42-mediated transformation. More recently, an integrative analysis of genomic, transcriptomic, and proteomic data from early stage and chemo-refractory lung adenocarcinoma demonstrated that KRAS mutant lung cancer can be classified into three subgroups by cooccurring genetic alterations in STK11, TP53, and CDKN2A/B [161].…”

Section: Studies On Clinical Specimens and Clinical Trialsmentioning

confidence: 99%

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Fang¹

2016

ABBS

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Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine.

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“…Cox et al [14] provide a nice summary of KRAS synthetic lethal genes. However, two major challenges must be tackled before this method can be widely and effectively exploited: (1) synthetic interactions appear to be context dependent and tissue specific [66,67], therefore, an improved screening method is needed [14]; and (2) some identified targets such as the transcription factor GATA2 are themselves undruggable, therefore, it can be challenging in some situations to find appropriate targeting strategies [68].…”

Section: Taking Advantage Of Synthetic Lethalitymentioning

confidence: 99%

Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities

Zhang

Park

Shin

et al. 2016

ABBS

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Oncogenic mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) occur in 15%-30% of non-small cell lung cancer (NSCLC). However, despite decades of intensive research, there is still no direct KRAS inhibitor with clinically proven efficacy. Considering its association with poor treatment response and prognosis of lung cancer, developing an effective inhibitory approach is urgently needed. Here, we review different strategies currently being explored to target KRAS-mutant NSCLC, discuss opportunities and challenges, and also propose some novel methods and concepts with the promise of clinical application.

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Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer

Cited by 157 publications

References 82 publications

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

FLIP: A Targetable Mediator of Resistance to Radiation in Non–Small Cell Lung Cancer

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities

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