Abstract
RAS has been shown to increase radiation resistance. Upstream and downstream pathways from RAS could thus be targets for manipulation of radiosensitivity. EGFR expression and AKT phosphorylation are also associated with the response to radiation. A retrospective study evaluating EGFR and AKT in patients treated with multimodality therapy found a significant association between P-AKT and treatment failure. Moreover, these data are strengthened by in vitro studies showing that inhibition of EGFR, RAS, PI3K, and AKT radiosensitized cancer cell lines. We have previously shown that PI3K is a mediator of RAS-induced radiation resistance. We now suggest that EGFR, which is upstream of PI3K, may also mediate resistance through a common pathway. In addition to EGFR and RAS, PTEN can also regulate the PI3K pathway. Identifying a common signal for EGFR, RAS, or PTEN that results in radiation resistance may uncover targets for developing molecular-based radiosensitization protocols for tumors resistant to radiation and thus improve local control.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ader I, Toulas C, Dalenc F, Delmas C, Bonnet J, Cohen-Jonathan E and Favre G . (2002). Oncogene, 21, 5998–6006.
Arase Y, Hiwasa T, Hasegawa R, Nomura J, Ito H and Suzuki N . (2000). Biochem. Biophys. Res. Commun., 267, 33–39.
Barabasi A-L . (2002). Linked: The New Science of Networks. Perseus: Cambridge, MA, p. 256.
Bernhard EJ, Kao G, Cox AD, Sebti SM, Hamilton AD, Muschel RJ and McKenna WG . (1996). Cancer Research, 56, 1727–1730.
Bernhard EJ, McKenna WG, Hamilton AD, Sebti SM, Qian Y, Wu JM and Muschel RJ . (1998). Cancer Res., 58, 1754–1761.
Bernhard EJ, Muschel RJ, Cohen-Jonathan E, Favre G, Hamilton AD, Sebti SM and McKenna WG . (2000). Prenyltransferase Inhibitors as Radiosensitizers. Humana Press: Totowa.
Bernhard EJ, Stanbridge EJ, Gupta S, Gupta AK, Soto D, Bakanauskas VJ, Cerniglia GJ, Muschel RJ and McKenna WG . (2000). Cancer Res., 60, 6597–6600.
Bonner JA, Raisch KP, Trummell HQ, Robert F, Meredith RF, Spencer SA, Buchsbaum DJ, Saleh MN, Stackhouse MA, LoBuglio AF, Peters GE, Carroll WR and Waksal HW . (2000). J. Clin. Oncol., 18, 47S–53S.
Brognard J, Clark AS, Ni Y and Dennis PA . (2001). Cancer Res., 61, 3986–3997.
Carpenter CL and Cantley LC . (1996). Curr. Opin. Cell Biol., 8, 153–158.
Cataldi A, Zauli G, Di Pietro R, Castorina S and Rana R . (2001). Cell. Signal, 13, 369–375.
Chan TO, Rodeck U, Chan AM, Kimmelman AC, Rittenhouse SE, Panayotou G and Tsichlis PN . (2002). Cancer Cell, 1, 181–191.
Coffer PJ, Jin J and Woodgett JR . (1998). Biochem. J., 335 (Partt 1), 1–13.
Cohen-Jonathan E, Muschel RJ, Gillies McKenna W, Evans SM, Cerniglia G, Mick R, Kusewitt D, Sebti SM, Hamilton AD, Oliff A, Kohl N, Gibbs JB and Bernhard EJ . (2000). Radiat. Res., 154, 125–132.
Delmas C, Heliez C, Cohen-Jonathan E, End D, Bonnet J, Favre G and Toulas C . (2002). Int. J. Cancer, 100, 43–48.
Downward J . (1998). Curr. Opin. Gene. Dev., 8, 49–54.
Downward J, Parker P and Waterfield MD . (1984). Nature, 311, 483–485.
Druker BJ . (2002a). Trends Mol. Med., 8, S14–S18.
Druker BJ . (2002b). Cancer Cell, 1, 31–36.
Edwards E, Geng L, Tan J, Onishko H, Donnelly E and Hallahan DE . (2002). Cancer Res., 62, 4671–4677.
Elion EA . (1998). Science, 281, 1625–1626.
FitzGerald TJ, Daugherty C, Kase K, Rothstein LA, McKenna M and Greenberger JS . (1985). Am. J. Clin. Oncol., 8, 517–522.
Gire V, Marshall C and Wynford-Thomas D . (2000). Oncogene, 19, 2269–2276.
Girinsky T, Lubin R, Pignon JP, Chavaudra N, Gazeau J, Dubray B, Cosset JM, Socie G and Fertil B . (1992). Int. J. Radiat. Oncol. Biol. Phys., 25, 3–7.
Gokhale PC, McRae D, Monia BP, Bagg A, Rahman A, Dritschilo A and Kasid U . (1999). Antisense Nucleic Acid Drug Dev., 9, 191–201.
Grana TM, Rusyn EV, Zhou H, Sartor CI and Cox AD . (2002). Cancer Res., 62, 4142–4150.
Grandis J, Melhem M, Gooding W, Day R, Holst V, Wagener M, Drenning S and Tweardy D . (1998). JNCI Cancer Spectrum, 90, 824–832.
Gupta AK, Bakanauskas VJ, Cerniglia GJ, Cheng Y, Bernhard EJ, Muschel RJ and McKenna WG . (2001a). Cancer Res., 61, 4278–4282.
Gupta AK, Bakanauskas VJ, McKenna WG, Bernhard EJ and Muschel RJ . (2001b). Methods Enzymol., 333, 284–290.
Gupta AK, Bernhard EJ, Bakanauskas VJ, Wu J, Muschel RJ and McKenna WG . (2000). Radiat. Res., 154, 64–72.
Gupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, Machtay M, Rosenthal DI, Bakanauskas VJ, Cerniglia GJ, Bernhard EJ, Weber RS and Muschel RJ . (2002). Clin. Cancer Res., 8, 885–892.
Hagan M, Wang L, Hanley JR, Park JS and Dent P . (2000). Radiat. Res., 153, 371–383.
Hahn SM, Bernhard EJ, Regine W, Mohiuddin M, Haller DG, Stevenson JP, Smith D, Pramanik B, Tepper J, DeLaney TF, Kiel KD, Morrison B, Deutsch P, Muschel RJ and McKenna WG . (2002). Clin. Cancer Res., 8, 1065–1072.
Hahn SMK, Morrison BW, Mohiuddin MM, Thomas D, Smith D, Brown R, Pramanik B, Kher U, Deutsch P and McKenna WG . (2000). Clin. Cancer Res., 8, 1065–1072.
Harari PM and Huang SM . (2001). Int. J. Radiat. Oncol. Biol. Phys., 49, 427–433.
Harari PM and Huang SM . (2002). Semin. Radiat. Oncol., 12, 21–26.
Henderson L, Weintraub B and Martin C . (2002). Disappointing Iressa Results. Btech News Vol. 2002 Btech Investor Inc. http://www.biospace.com/news_story.cfm?StoryID=975320&full-1&print=1.
Jaumot M, Yan J, Clyde-Smith J, Sluimer J and Hancock JF . (2002). J. Biol. Chem., 277, 272–278.
Kasid U, Pfeifer A, Brennan T, Beckett M, Weichselbaum RR, Dritschilo A and Mark GE . (1989). Science, 243, 1354–1356.
Kasid U, Pfeifer A, Weichselbaum RR, Dritschilo A and Mark GE . (1987). Science, 237, 1039–1041.
Kasid U, Pirollo K, Dritschilo A and Chang E . (1993). Adv. Cancer Res., 61, 195–233.
Kasid U, Suy S, Dent P, Ray S, Whiteside TL and Sturgill TW . (1996). Nature, 382, 813–816.
Klapper LN, Kirschbaum MH, Sela M and Yarden Y . (2000). Adv. Cancer Res., 77, 25–79.
Krasilnikov M, Adler V, Fuchs SY, Dong Z, Haimovitz-Friedman A, Herlyn M and Ronai Z . (1999). Mol. Carcinog., 24, 64–69.
Leyland-Jones B . (2002). Lancet Oncol., 3, 137–144.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH and Parsons R . (1997). Science, 275, 1943–1947.
Li Q and Zhu GD . (2002). Curr. Top. Med. Chem., 2, 939–971.
Ling CC and Endlich B . (1989). Radiat. Res., 120, 267–279.
Maehama T and Dixon JE . (1998). J. Biol. Chem., 273, 13375–13378.
McKenna SL and Cotter TG . (1997). Adv. Cancer Res., 71, 121–164.
McKenna WG, Muschel RJ, Gupta AK, Hahn SM and Bernhard EJ . (2002). Semin. Radiat. Oncol., 12, 27–32.
McKenna WG, Weiss MA, Bakanauskas VJ, Sandler H, Kelsten M, Biaglow J, Endlich B, Ling C and Muschel RJ . (1990a). Int. J. Rad. Onc. Biol. Phys., 18, 849–860.
McKenna WG, Weiss MC, Endlich B, Ling CC, Bakanauskas VJ, Kelsten ML and Muschel RJ . (1990b). Cancer Res., 50, 97–102.
Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K, Mendelsohn J and Fan Z . (2000). Clin. Cancer Res., 6, 701–708.
Miller AC, Kariko K, Myers CE, Clark EP and Samid D . (1993). Int. J. Cancer, 53, 302–307.
Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW and Kremer H . (1997). Hum. Mol. Genet., 6, 1383–1387.
Nicholson KM and Anderson NG . (2002). Cell. Signal, 14, 381–395.
O'Dwyer ME, Mauro MJ and Druker BJ . (2002). Annu. Rev. Med., 53, 369–381.
O'Rourke DM, Kao GD, Singh N, Park B-W, Muschel RJ, Wu C-J and Greene MI . (1998). Proc. Natl. Acad. Sci. USA, 95, 10842–10847.
Pastan I and Kreitman RJ . (2002). Curr. Opin. Investig. Drugs, 3, 1089–1091.
Prior IA and Hancock JF . (2001). J. Cell. Sci 114, 1603–1608.
Prior IA, Harding A, Yan J, Sluimer J, Parton RG and Hancock JF . (2001). Nat. Cell Bio. 3, 368–375.
Rait A, Pirollo K, Will DW, Peyman A, Rait V, Uhlmann E and Chang EH . (2000). Bioconjug. Chem., 11, 153–160.
Reuther GW and Der CJ . (2000). Curr. Opin. Cell Biol., 12, 157–165.
Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA, Khazaeli MB, Saleh MN, Carey D, LoBuglio AF, Wheeler RH, Cooper MR and Waksal HW . (2001). J. Clin. Oncol., 19, 3234–3243.
Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD and Downward J . (1994). Nature, 370, 527–532.
Russell JS, Lang FF, Huet T, Janicot M, Chada S, Wilson DR and Tofilon PJ . (1999). Radiosensitization of human tumor cell lines induced by the adenovirus- mediated expression of an anti-Ras single-chain antibody fragment, 59, 5239–5244.
Russell JS, Raju U, Gumin GJ, Lang FF, Wilson DR, Huet T and Tofilon PJ . (2002). Cancer Res., 62, 2318–2326.
Shao X, Tandon R, Samara G, Kanki H, Yano H, Close LG, Parsons R and Sato T . (1998). Int. J. Cancer, 77, 684–688.
Sheridan MT, O'Dwyer T, Seymour CB and Mothersill CE . (1997). Radiat. Oncol. Investig., 5, 180–186.
Shin D, Ro J, Hong W and Hittelman W . (1994). Cancer Res., 54, 3153–3159.
Sklar MD . (1988). Science, 239, 645–647.
Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, Liu DD, Kurie JM, Mao L and Khuri FR . (2002). Clin. Cancer Res., 8, 1178–1184.
Testa JR and Bellacosa A . (2001). Proc. Natl. Acad. Sci. USA, 98, 10983–10985.
Tezuka M, Watanabe H, Nakamura S, Yu D, Aung W, Sasaki T, Shibuya H and Miura M . (2001). Clin. Cancer Res., 7, 3206–3214.
Thakkar H, Chen X, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N and Srivastava RK . (2001). J. Biol. Chem., 276, 38361–38369.
Thomssen C . (2001). Anticancer Drugs, 12, S19–S25.
Van Meer G . (2002). Science, 296, 855–857.
West CM, Davidson SE, Burt PA and Hunter RD . (1995). Int. J. Rad. Onc., 31, 841–846.
West CM, Davidson SE, Hendry JH and Hunter RD . (1991). Lancet, 338, 818.
West CM, Davidson SE, Roberts SA and Hunter RD . (1993). Br. J. Cancer, 68, 819–823.
Workman P . (2001). Curr. Cancer Drug. Targets, 1, 33–47.
Zacharias DA, Violin JD, Newton AC and Tsien RY . (2002). Science, 296, 913–916.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by NCI Grant PO1 CA 75138
Rights and permissions
About this article
Cite this article
Gillies McKenna, W., Muschel, R., Gupta, A. et al. The RAS signal transduction pathway and its role in radiation sensitivity. Oncogene 22, 5866–5875 (2003). https://doi.org/10.1038/sj.onc.1206699
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206699
Keywords
This article is cited by
-
KRASG12C inhibition using MRTX1257: a novel radio-sensitizing partner
Journal of Translational Medicine (2023)
-
Precision radiotherapy for non-small cell lung cancer
Journal of Biomedical Science (2020)
-
mTORC1 inhibitor RAD001 (everolimus) enhances non-small cell lung cancer cell radiosensitivity in vitro via suppressing epithelial–mesenchymal transition
Acta Pharmacologica Sinica (2019)
-
FDG PET/CT radiomics for predicting the outcome of locally advanced rectal cancer
European Journal of Nuclear Medicine and Molecular Imaging (2018)
-
Can tumor regression grade influence survival outcome in ypT3 rectal cancer?
Clinical and Translational Oncology (2016)