Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in <i>LKB1</i>-Mutant Lung Cancer

Liu, Yan; Marks, Kevin M.; Cowley, Glenn S.; Carretero, Julián; Liu, Qingsong; Nieland, Thomas J.F.; Xu, Chunxiao; Cohoon, Travis J.; Gao, Peng; Zhang, Yong; Chen, Zhao; Altabef, Abigail; Tchaicha, Jeremy H.; Wang, Xiaoxu; Choe, Sung; Driggers, Edward M.; Zhang, Jianming; Bailey, Sean T.; Sharpless, Norman E.; Hayes, D. Neil; Patel, Nirali M.; Jänne, Pasi A.; Bardeesy, Nabeel; Engelman, Jeffrey A.; Manning, Brendan D.; Shaw, Reuben J.; Asara, John M.; Scully, Ralph; Kimmelman, Alec C.; Byers, Lauren A.; Gibbons, Don L.; Wistuba, Ignacio I.; Heymach, John V.; Kwiatkowski, David J.; Kim, William Y.; Kung, Andrew L.; Gray, Nathanael S.; Root, David E.; Cantley, Lewis C.; Wong, Kwok-Kin

doi:10.1158/2159-8290.cd-13-0015

Cited by 131 publications

(142 citation statements)

References 35 publications

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“…Liu and colleagues have recently indicated that LKB1-mutant lung cancers are vulnerable in nucleotide biosynthesis pathways and sensitive to deoxythymidylate kinase inhibition (28). Therefore, targeting CPS1 in combination with deoxythymidylate kinase also might have promising therapeutic potential in LKB1-inactivated LADC.…”

Section: Discussionmentioning

confidence: 99%

“…interfere with DNA synthesis pathways and are frequently used to treat LADC (27), as well as with CHK1 inhibitor AZD7762, to which LKB1-deficient lung cancer was recently shown to be sensitive (28). CPS1 knockdown showed statistically significant additive effects in all drug combinations in the LKB1-inactivated cell lines H1437 and H1944 ( Figure 3C) but not in the LKB1-intact cell line H2009, indicating the potential of CPS1 as a therapeutic target alone or combined with these conventional chemotherapy agents or with DNA damage checkpoint inhibitors in LKB1-inactivated LADC.…”

Section: Articlementioning

confidence: 99%

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Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Çeliktaş

Tanaka

Tripathi

et al. 2016

JNCI J Natl Cancer Inst

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Background: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first ratelimiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided. Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7% of LKB1-negative LADC, and only 5.0% of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio ¼ 3.03, 95% confidence interval ¼ 1.74 to 5.25, P < .001). Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.

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Section: Discussionmentioning

confidence: 99%

Section: Articlementioning

confidence: 99%

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Çeliktaş

Tanaka

Tripathi

et al. 2016

JNCI J Natl Cancer Inst

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“…Our cDNA rescue experiments demonstrate that the catalytic activity of Ubc9 is critical for KRAS transformation, thus suggesting small molecule inhibitors against Ubc9 might be effective at attenuating the growth of KRAS mutant tumors. Of note, it has been reported that Ubc9 can be targeted by small molecule inhibitors (35). Although inhibition of Ubc9 is likely to perturb the function of a large number of cellular processes, a therapeutic window could exist for those cancer cells exhibiting nononcogene addiction to this pathway.…”

Section: Discussionmentioning

confidence: 99%

Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9

Swatkoski

Holly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The small GTPase KRAS is frequently mutated in human cancer and currently there are no targeted therapies for KRAS mutant tumors. Here, we show that the small ubiquitin-like modifier (SUMO) pathway is required for KRAS-driven transformation. RNAi depletion of the SUMO E2 ligase Ubc9 suppresses 3D growth of KRAS mutant colorectal cancer cells in vitro and attenuates tumor growth in vivo. In KRAS mutant cells, a subset of proteins exhibit elevated levels of SUMOylation. Among these proteins, KAP1, CHD1, and EIF3L collectively support anchorage-independent growth, and the SUMOylation of KAP1 is necessary for its activity in this context. Thus, the SUMO pathway critically contributes to the transformed phenotype of KRAS mutant cells and Ubc9 presents a potential target for the treatment of KRAS mutant colorectal cancer.he Ras family of small GTPases are signal transduction molecules downstream of growth factor receptors. Ras activates a number of downstream effector pathways to regulate cell proliferation, survival and motility, these effectors include the MAP kinase (MAPK) pathway, the PI3-kinase (PI3K) pathway, the small GTPases RalA, RalB, and Rho, and phospholipase-Ce (1). Activating mutations in Ras are frequently found in human malignancies, with mutations in the KRAS gene being particularly prevalent. KRAS mutations occur in ∼60% of pancreatic ductal carcinomas, 26% of lung adenocarcinomas, and 45% of colorectal carcinomas, as well as a significant fraction of ovarian, endometrial, and biliary track cancers (2, 3). A salient hallmark of the Ras oncogene is its ability to transform cells to enable anchorage-independent 3D colony growth in vitro and tumor growth in vivo. Consequently, Ras mutant cancer cells often exhibit oncogene addiction to Ras such that extinction of the Ras oncogene leads to either a reversion of the transformed phenotype or loss of viability (4, 5). Therapeutically, the Ras oncoprotein has proven pharmacologically intractable thus far: intensive drug screening efforts have not yielded high-affinity, selective Ras inhibitors. Farnesyltransferase inhibitors that aimed to block Ras membrane localization are ineffective against KRAS because of its alternative geranylgeranylation. Inhibitors targeting Ras effector kinases, including MEK, PI3K, and Akt, are currently undergoing clinical evaluations, but they have yet to demonstrate clear clinical benefits (6). Thus, KRAS mutant tumors represent a class of "recalcitrant cancer" with urgent, unmet therapeutic needs.To gain new insight into the genetic dependencies of Ras mutant cancers and discover new therapeutic targets, we and others have previously carried out genome-wide synthetic lethal screens in KRAS mutant and WT cells to identify genes whose depletion leads to greater toxicity in KRAS mutant cells. In our screen we found a wide array of genes, many of which are involved in cellular stress response, that are required to maintain the viability of KRAS mutant cells (7). We proposed the concept of "nononcogene addiction" to explain the heig...

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“…These gene sets include tumor-suppressor genes, such as TP53, CDKN2A, KEAP1, and STK11/LKB1, and chromatin remodeling/modifying genes, such as ARID1A and SMARCA4, which are the targets of genetic loss-of-function aberrations in cancer cells (20). Notably, recent studies suggested that these deleterious aberrations are therapeutically targetable; drugs restoring the function of mutant p53 proteins are being developed (21,22), and synthetic lethalitybased therapies have been considered by us and others to treat cancers with TP53, LKB1, ARID1A, and SMARCA4 deficiencies (23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Development of Lung Adenocarcinomas with Exclusive Dependence on Oncogene Fusions

Saito

Shimada²,

Shiraishi³

et al. 2015

Cancer Research

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This report delivers a comprehensive genetic alteration profile of lung adenocarcinomas (LADC) driven by ALK, RET, and ROS1 oncogene fusions. These tumors are difficult to study because of their rarity. Each drives only a low percentage of LADCs. Whole-exome sequencing and copy-number variation analyses were performed on a Japanese LADC cohort (n ¼ 200) enriched in patients with fusions (n ¼ 31, 15.5%), followed by deep resequencing for validation. The driver fusion cases showed a distinct profile with smaller numbers of nonsynonymous mutations in cancer-related genes or truncating mutations in SWI/SNF chromatin remodeling complex genes than in other LADCs (P < 0.0001). This lower mutation rate was independent of age, gender, smoking status, pathologic stage, and tumor differentiation (P < 0.0001) and was validated in nine fusion-positive cases from a U.S. LADCs cohort (n ¼ 230). In conclusion, our findings indicate that LADCs with ALK, RET, and ROS1 fusions develop exclusively via their dependence on these oncogene fusions. The presence of such few alterations beyond the fusions supports the use of monotherapy with tyrosine kinase inhibitors targeting the fusion products in fusion-positive LADCs. Cancer Res; 75(11); 2264-71. Ó2015 AACR.

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Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer

Cited by 131 publications

References 35 publications

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9

Development of Lung Adenocarcinomas with Exclusive Dependence on Oncogene Fusions

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