TY - JOUR
T1 - Synthetic lethal kinases in Ras/p53 mutant squamous cell carcinoma
AU - Moser, Russell
AU - Gurley, Kay E.
AU - Nikolova, Olga
AU - Qin, Guangrong
AU - Joshi, Rashmi
AU - Mendez, Eduardo
AU - Shmulevich, Ilya
AU - Ashley, Amanda
AU - Grandori, Carla
AU - Kemp, Christopher J.
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/6/10
Y1 - 2022/6/10
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-022-02330-w
DO - 10.1038/s41388-022-02330-w
M3 - Article
C2 - 35538224
AN - SCOPUS:85129740576
VL - 41
SP - 3355
EP - 3369
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 24
ER -