Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Synthetic lethal kinases in Ras/p53 mutant squamous cell carcinoma

Oncogene volume 41, pages 3355–3369 (2022)Cite this article

Subjects

Abstract

The oncogene Ras and the tumor suppressor gene p53 are frequently co-mutated in human cancer and mutations in Ras and p53 can cooperate to generate a more malignant cell state. To discover novel druggable targets for cancers carrying co-mutations in Ras and p53, we performed arrayed, kinome focused siRNA and oncology drug phenotypic screening utilizing a set of syngeneic Ras mutant squamous cell carcinoma (SCC) cell lines that also carried co-mutations in selected p53 pathway genes. These cell lines were derived from SCCs from carcinogen-treated inbred mice which harbored germline deletions or mutations in Trp53, p19Arf, Atm, or Prkdc. Both siRNA and drug phenotypic screening converge to implicate the phosphoinositol kinases, receptor tyrosine kinases, MAP kinases, as well as cell cycle and DNA damage response genes as targetable dependencies in SCC. Differences in functional kinome profiles between Ras mutant cell lines reflect incomplete penetrance of Ras synthetic lethal kinases and indicate that co-mutations cause a rewiring of survival pathways in Ras mutant tumors. This study describes the functional kinomic landscape of Ras/p53 mutant chemically-induced squamous cell carcinoma in both the baseline unperturbed state and following DNA damage and nominates candidate therapeutic targets, including the Nek4 kinase, for further development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Kinome dependencies in tumor cells derived from DMBA/TPA induced squamous cell carcinomas.
Fig. 2: Fitness profiles of protein kinase C and phosphoinositol kinase family members in five mSCC cell lines.
Fig. 3: Nominated targets for Hras Q61L mutant SCC.
Fig. 4: Differential dependencies in HrasQ61L Trp53+/+ vs. HrasQ61L Trp53−/− cells.
Fig. 5: Oncology drug profiling of SCC cells.
Fig. 6: Confirmation of Hras and Nek4 dependencies in SCC cells.

Similar content being viewed by others

References

  1. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Prior IA, Hood FE, Hartley JL. The frequency of ras mutations in cancer. Cancer Res. 2020;80:2969–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19:533–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Abel EL, Angel JM, Kiguchi K, DiGiovanni J. Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications. Nat Protoc. 2009;4:1350–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kemp CJ. Animal models of chemical carcinogenesis: driving breakthroughs in cancer research for 100 years. In: Abate-Shen C, Politi K, Chodosh LA, Olive KP (eds). Mouse models of cancer: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2014. pp. 51–60.

  6. Balmain A, Pragnell IB. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature. 1983;303:72–4.

    Article  CAS  PubMed  Google Scholar 

  7. McCreery MQ, Halliwill KD, Chin D, Delrosario R, Hirst G, Vuong P, et al. Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers. Nat Med. 2015;21:1514–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kemp CJ. Multistep skin cancer in mice as a model to study the evolvability of cancer cells. Sem Cancer Biol. 2005;15:460–73.

    Article  CAS  Google Scholar 

  9. Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983;304:596–602.

    Article  CAS  PubMed  Google Scholar 

  10. Ruley HE. Adenovirus early region E1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983;304:602–6.

    Article  CAS  PubMed  Google Scholar 

  11. Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, et al. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002;22:3497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lin AW, Lowe SW. Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation. Proc Natl Acad Sci USA. 2001;98:5025–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nassar D, Latil M, Boeckx B, Lambrechts D, Blanpain C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat Med. 2015;21:946–54.

    Article  CAS  PubMed  Google Scholar 

  14. Kemp CJ, Donehower LA, Bradley A, Balmain A. Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell. 1993;74:813–22.

    Article  CAS  PubMed  Google Scholar 

  15. Kelly-Spratt KS, Gurley KE, Yasui Y, Kemp CJ. p19Arf suppresses growth, progression, and metastasis of Hras-driven carcinomas through p53-dependent and -independent pathways. PLoS Biol. 2004;2:1138–49.

    Article  CAS  Google Scholar 

  16. Ehrenreiter K, Kern F, Velamoor V, Meissl K, Galabova-Kovacs G, Sibilia M, et al. Raf-1 addiction in Ras-induced skin carcinogenesis. Cancer Cell. 2009;16:149–60.

    Article  CAS  PubMed  Google Scholar 

  17. Bai Y, Edamatsu H, Maeda S, Saito H, Suzuki N, Satoh T, et al. Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res. 2004;64:8808–10.

    Article  CAS  PubMed  Google Scholar 

  18. Jameson KL, Mazur PK, Zehnder AM, Zhang J, Zarnegar B, Sage J, et al. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nat Med. 2013;19:626–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Malliri A, van der Kammen RA, Clark K, van d V, Michiels F, Collard JG. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature. 2002;417:867–71.

    Article  CAS  PubMed  Google Scholar 

  20. McLean GW, Komiyama NH, Serrels B, Asano H, Reynolds L, Conti F, et al. Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes Dev. 2004;18:2998–3003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sterneck E, Zhu S, Ramirez A, Jorcano JL, Smart RC. Conditional ablation of C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis. Oncogene. 2006;25:1272–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Saez E, Rutberg SE, Mueller E, Oppenheim H, Smoluk J, Yuspa SH, et al. c-fos is required for malignant progression of skin tumors. Cell. 1995;82:721–32.

    Article  CAS  PubMed  Google Scholar 

  23. Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R, et al. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA. 1999;96:9827–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J, et al. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Investig. 2004;114:720–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Robles AI, Rodriguez-Puebla ML, Glick AB, Trempus C, Hansen L, Sicinski P, et al. Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev. 1998;12:2469–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Martin TD, Cook DR, Choi MY, Li MZ, Haigis KM, Elledge SJ. A role for mitochondrial translation in promotion of viability in K-Ras mutant cells. Cell Rep. 2017;20:427–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ryan CJ, Bajrami I, Lord CJ. Synthetic lethality and cancer—penetrance as the major barrier. Trends Cancer. 2018;4:671–83.

    Article  CAS  PubMed  Google Scholar 

  28. Bailey SL, Gurley KE, Hoon-Kim K, Kelly-Spratt KS, Kemp CJ. Tumor suppression by p53 in the absence of Atm. Mol Cancer Res. 2008;6:1185–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kemp CJ, Vo K, Gurley KE. Resistance to skin tumorigenesis in DNAPK-deficient SCID mice is not due to immunodeficiency but results from hypersensitivity to TPA-induced apoptosis. Carcinogenesis. 1999;20:2051–6.

    Article  CAS  PubMed  Google Scholar 

  30. Mackay HJ, Twelves CJ. Targeting the protein kinase C family: are we there yet? Nat Rev Cancer. 2007;7:554–62.

    Article  CAS  PubMed  Google Scholar 

  31. Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982;257:7847–51.

    Article  CAS  PubMed  Google Scholar 

  32. Reddig PJ, Dreckschmidt NE, Zou J, Bourguignon SE, Oberley TD, Verma AK. Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. Cancer Res. 2000;60:595–602.

    CAS  PubMed  Google Scholar 

  33. Hara T, Saito Y, Hirai T, Nakamura K, Nakao K, Katsuki M, et al. Deficiency of protein kinase Calpha in mice results in impairment of epidermal hyperplasia and enhancement of tumor formation in two-stage skin carcinogenesis. Cancer Res. 2005;65:7356–62.

    Article  CAS  PubMed  Google Scholar 

  34. Parker PJ, Brown SJ, Calleja V, Chakravarty P, Cobbaut M, Linch M, et al. Equivocal, explicit and emergent actions of PKC isoforms in cancer. Nat Rev Cancer. 2021;21:51–60.

  35. Antal CE, Hudson AM, Kang E, Zanca C, Wirth C, Stephenson NL, et al. Cancer-associated protein kinase C mutations reveal kinase’s role as tumor suppressor. Cell. 2015;160:489–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Segrelles C, Ruiz S, Perez P, Murga C, Santos M, Budunova IV, et al. Functional roles of Akt signaling in mouse skin tumorigenesis. Oncogene. 2002;21:53–64.

    Article  CAS  PubMed  Google Scholar 

  37. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell. 2007;128:295–308.

    Article  CAS  PubMed  Google Scholar 

  38. Yadav V, Denning MF. Fyn is induced by Ras/PI3K/Akt signaling and is required for enhanced invasion/migration. Mol Carcinog. 2011;50:346–52.

    Article  CAS  PubMed  Google Scholar 

  39. Weinberg F, Reischmann N, Fauth L, Taromi S, Mastroianni J, Kohler M, et al. The atypical kinase RIOK1 promotes tumor growth and invasive behavior. EBioMedicine. 2017;20:79–97.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Eyers PA, Keeshan K, Kannan N. Tribbles in the 21st century: the evolving roles of tribbles pseudokinases in biology and disease. Trends Cell Biol. 2017;27:284–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kiessling MK, Schuierer S, Stertz S, Beibel M, Bergling S, Knehr J, et al. Identification of oncogenic driver mutations by genome-wide CRISPR-Cas9 dropout screening. BMC Genom. 2016;17:723.

    Article  CAS  Google Scholar 

  42. Costa-Cabral S, Brough R, Konde A, Aarts M, Campbell J, Marinari E, et al. CDK1 is a synthetic lethal target for KRAS mutant tumours. PLoS ONE. 2016;11:e0149099.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462:108–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002;12:258–66.

    Article  CAS  PubMed  Google Scholar 

  45. Cox AD, Der CJ, Philips MR. Targeting RAS membrane association: back to the future for anti-RAS drug discovery? Clin Cancer Res. 2015;21:1819–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Moser R, Xu C, Kao M, Annis J, Lerma LA, Schaupp CM, et al. Functional kinomics identifies candidate therapeutic targets in head and neck cancer. Clin Cancer Res. 2014;20:4274–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xu C, Nikolova O, Basom RS, Mitchell RM, Shaw R, Moser RD, et al. Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer. Clin Cancer Res. 2018;24:2828–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fry AM, O’Regan L, Sabir SR, Bayliss R. Cell cycle regulation by the NEK family of protein kinases. J Cell Sci. 2012;125:4423–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Pavan ICB, Peres de Oliveira A, Dias PRF, Basei FL, Issayama LK, Ferezin CC, et al. On broken ne(c)ks and broken DNA: the role of human NEKs in the DNA damage response. Cells. 2021;10:1–25.

  50. Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49:1779–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a cancer dependency map. Cell. 2017;170:564–76.e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ise K, Nakamura K, Nakao K, Shimizu S, Harada H, Ichise T, et al. Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene. 2000;19:2951–6.

    Article  CAS  PubMed  Google Scholar 

  53. Dlugosz AA, Hansen L, Cheng C, Alexander N, Denning MF, Threadgill DW, et al. Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras(Ha) oncogene but does not block in vitro keratinocyte responses to oncogenic ras. Cancer Res. 1997;57:3180–8.

    CAS  PubMed  Google Scholar 

  54. Dahlhoff M, Muzumdar S, Schafer M, Schneider MR. ERBB2 is essential for the growth of chemically induced skin tumors in mice. J Investig Dermatol. 2017;137:921–30.

    Article  CAS  PubMed  Google Scholar 

  55. Dahlhoff M, Schafer M, Muzumdar S, Rose C, Schneider MR. ERBB3 is required for tumor promotion in a mouse model of skin carcinogenesis. Mol Oncol. 2015;9:1825–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Reddig PJ, Dreckschmidt NE, Ahrens H, Simsiman R, Tseng CP, Zou J, et al. Transgenic mice overexpressing protein kinase Cdelta in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 1999;59:5710–8.

    CAS  PubMed  Google Scholar 

  57. Adhikari H, Counter CM. Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability. Nat Commun. 2018;9:3646.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Burke JE. Structural basis for regulation of phosphoinositide kinases and their involvement in human disease. Mol Cell. 2018;71:653–73.

    Article  CAS  PubMed  Google Scholar 

  59. Choi S, Thapa N, Tan X, Hedman AC, Anderson RA. PIP kinases define PI4,5P(2)signaling specificity by association with effectors. Biochim Biophys Acta. 2015;1851:711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576–82.

    Article  CAS  Google Scholar 

  61. Toyoshima M, Howie HL, Imakura M, Walsh RM, Annis JE, Chang AN, et al. Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc Natl Acad Sci USA. 2012;109:9545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tsunoda N, Kokuryo T, Oda K, Senga T, Yokoyama Y, Nagino M, et al. Nek2 as a novel molecular target for the treatment of breast carcinoma. Cancer Sci. 2009;100:111–6.

    Article  CAS  PubMed  Google Scholar 

  63. Moniz L, Dutt P, Haider N, Stambolic V. Nek family of kinases in cell cycle, checkpoint control and cancer. Cell Div. 2011;6:1–10.

    Article  CAS  Google Scholar 

  64. Doles J, Hemann MT. Nek4 status differentially alters sensitivity to distinct microtubule poisons. Cancer Res. 2010;70:1033–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nguyen CL, Possemato R, Bauerlein EL, Xie A, Scully R, Hahn WC. Nek4 regulates entry into replicative senescence and the response to DNA damage in human fibroblasts. Mol Cell Biol. 2012;32:3963–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ding NH, Zhang L, Xiao Z, Rong ZX, Li Z, He J, et al. NEK4 kinase regulates EMT to promote lung cancer metastasis. J Cell Mol Med. 2018;22:5877–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Park SJ, Jo DS, Jo SY, Shin DW, Shim S, Jo YK, et al. Inhibition of never in mitosis A (NIMA)-related kinase-4 reduces survivin expression and sensitizes cancer cells to TRAIL-induced cell death. Oncotarget. 2016;7:65957–67.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Keith WN, Mee PJ, Brown R. Response of mouse skin tumors to doxorubicin is dependent on carcinogen exposure. Cancer Res. 1990;50:6841–7.

    CAS  PubMed  Google Scholar 

  69. Mendez E, Rodriguez CP, Kao MC, Raju S, Diab A, Harbison RA, et al. A phase I clinical trial of AZD1775 in combination with neoadjuvant weekly docetaxel and cisplatin before definitive therapy in head and neck squamous cell carcinoma. Clin Cancer Res. 2018;24:2740–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pilie PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16:81–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M, et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell. 2003;4:111–20.

    Article  CAS  PubMed  Google Scholar 

  72. Schneider G, Schmidt-Supprian M, Rad R, Saur D. Tissue-specific tumorigenesis: context matters. Nat Rev Cancer. 2017;17:239–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hahn WC, Bader JS, Braun TP, Califano A, Clemons PA, Druker BJ, et al. An expanded universe of cancer targets. Cell. 2021;184:1142–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Nowak JA, Fuchs E. Isolation and culture of epithelial stem cells. Methods Mol Biol. 2009;482:215–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Burns PA, Kemp CJ, Gannon JV, Lane DP, Bremner R, Balmain A. Loss of heterozygosity and mutational alterations of the p53 gene in skin tumors of interspecific hybrid mice. Oncogene. 1991;6:2363–9.

    CAS  PubMed  Google Scholar 

  76. Araki R, Fujimori A, Hamatani K, Mita K, Saito T, Mori M, et al. Nonsense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice. Proc Natl Acad Sci USA. 1997;94:2438–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang JH, Chung TD, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen. 1999;4:67–73.

    Article  CAS  PubMed  Google Scholar 

  78. Birmingham A, Selfors LM, Forster T, Wrobel D, Kennedy CJ, Shanks E, et al. Statistical methods for analysis of high-throughput RNA interference screens. Nat Methods. 2009;6:569–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ghandi M, Huang FW, Jane-Valbuena J, Kryukov GV, Lo CC, McDonald ER 3rd, et al. Next-generation characterization of the cancer cell line encyclopedia. Nature. 2019;569:503–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by The Hartwell Fund, NCI U01 CA176303, U01 CA217883, U54 CA132381, R01 CA214428, R01 CA215647, 2P30CA015704, and ACS 123653-RSG-13-066. We acknowledge technical assistance from Slobodan Beronja in generating normal mouse keratinocytes and the use of data from the NCI’s Cancer Target Discovery and Development Network, The Cancer Genome Atlas, and The Cell Line Encyclopedia.

Author information

Author notes

  1. Deceased: Eduardo Mendez.

Authors and Affiliations

  1. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Russell Moser, Kay E. Gurley & Christopher J. Kemp

  2. Division of Oncological Sciences, Oregon Health and Science University, Portland, OR, USA

    Olga Nikolova

  3. Institute for Systems Biology, Seattle, WA, USA

    Guangrong Qin & Ilya Shmulevich

  4. New Mexico State University, Las Cruces, NM, USA

    Rashmi Joshi & Amanda Ashley

  5. SEngine Precision Medicine, Seattle, WA, USA

    Carla Grandori

Authors
  1. Russell Moser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kay E. Gurley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olga Nikolova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guangrong Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rashmi Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eduardo Mendez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ilya Shmulevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amanda Ashley
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carla Grandori
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher J. Kemp
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RM, KEG, and RJ performed experiments, ON, GQ, performed data analysis, EM, IS, AA, CG, and CJK designed and supervised experiments and all authors contributed to manuscript preparation.

Corresponding author

Correspondence to Christopher J. Kemp.

Ethics declarations

Competing interests

CJK and CG are founders and stockholders in SEngine Precision Medicine. All other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moser, R., Gurley, K.E., Nikolova, O. et al. Synthetic lethal kinases in Ras/p53 mutant squamous cell carcinoma. Oncogene 41, 3355–3369 (2022). https://doi.org/10.1038/s41388-022-02330-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02330-w

Search

Advanced search

Quick links