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A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin.

Xia Y, Liu YL, Xie Y, Zhu W, Guerra F, Shen S, Yeddula N, Fischer W, Low W, Zhou X, Zhang Y, Oldfield E, Verma IM
Sci Transl Med 6 263ra161 (2014)
Cited: 28 times
EuropePMC logo PMID: 25411474

Abstract

Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not been successfully targeted. We describe a combination therapy for treating these malignancies with two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D-induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding proteins) critical for tumor growth and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant nuclear factor κB (NF-κB) activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mammalian target of rapamycin (mTOR) pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.

Articles - 4n1z mentioned but not cited (1)

  1. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Xia Y, Liu YL, Xie Y, Zhu W, Guerra F, Shen S, Yeddula N, Fischer W, Low W, Zhou X, Zhang Y, Oldfield E, Verma IM. Sci Transl Med 6 263ra161 (2014)


Reviews citing this publication (8)

  1. Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer. Liu G, Pei F, Yang F, Li L, Amin AD, Liu S, Buchan JR, Cho WC. Int J Mol Sci 18 E367 (2017)
  2. RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies. Fang B. Acta Biochim Biophys Sin (Shanghai) 48 27-38 (2016)
  3. Bisphosphonate-Functionalized Imaging Agents, Anti-Tumor Agents and Nanocarriers for Treatment of Bone Cancer. Nadar RA, Margiotta N, Iafisco M, van den Beucken JJJP, Boerman OC, Leeuwenburgh SCG. Adv Healthc Mater 6 (2017)
  4. K-Ras prenylation as a potential anticancer target. Baranyi M, Buday L, Hegedűs B. Cancer Metastasis Rev 39 1127-1141 (2020)
  5. Molecular mechanisms linking geranylgeranyl diphosphate synthase to cell survival and proliferation. Agabiti SS, Liang Y, Wiemer AJ. Mol Membr Biol 33 1-11 (2016)
  6. Autophagy-related signaling pathways in non-small cell lung cancer. Wang J, Gong M, Fan X, Huang D, Zhang J, Huang C. Mol Cell Biochem 477 385-393 (2022)
  7. Targeting prenylation inhibition through the mevalonate pathway. Manaswiyoungkul P, de Araujo ED, Gunning PT. RSC Med Chem 11 51-71 (2020)
  8. Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target. Muehlebach ME, Holstein SA. Clin Transl Med 13 e1167 (2023)

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  2. Heterochromatin-Encoded Satellite RNAs Induce Breast Cancer. Zhu Q, Hoong N, Aslanian A, Hara T, Benner C, Heinz S, Miga KH, Ke E, Verma S, Soroczynski J, Yates JR, Hunter T, Verma IM. Mol Cell 70 842-853.e7 (2018)
  3. Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis. Burikhanov R, Hebbar N, Noothi SK, Shukla N, Sledziona J, Araujo N, Kudrimoti M, Wang QJ, Watt DS, Welch DR, Maranchie J, Harada A, Rangnekar VM. Cell Rep 18 508-519 (2017)
  4. mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer. Liang SQ, Bührer ED, Berezowska S, Marti TM, Xu D, Froment L, Yang H, Hall SRR, Vassella E, Yang Z, Kocher GJ, Amrein MA, Riether C, Ochsenbein AF, Schmid RA, Peng RW. Oncogene 38 622-636 (2019)
  5. The red wine component ellagic acid induces autophagy and exhibits anti-lung cancer activity in vitro and in vivo. Duan J, Zhan JC, Wang GZ, Zhao XC, Huang WD, Zhou GB, Zhou GB. J Cell Mol Med 23 143-154 (2019)
  6. Anticancer Activity of Polyoxometalate-Bisphosphonate Complexes: Synthesis, Characterization, In Vitro and In Vivo Results. Boulmier A, Feng X, Oms O, Mialane P, Rivière E, Shin CJ, Yao J, Kubo T, Furuta T, Oldfield E, Dolbecq A. Inorg Chem 56 7558-7565 (2017)
  7. Bisphosphonate-Generated ATP-Analogs Inhibit Cell Signaling Pathways. Malwal SR, O'Dowd B, Feng X, Turhanen P, Shin C, Yao J, Kim BK, Baig N, Zhou T, Bansal S, Khade RL, Zhang Y, Oldfield E. J Am Chem Soc 140 7568-7578 (2018)
  8. Metformin exerts anti-AR-negative prostate cancer activity via AMPK/autophagy signaling pathway. Chen C, Wang H, Geng X, Zhang D, Zhu Z, Zhang G, Hou J. Cancer Cell Int 21 404 (2021)
  9. Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets. Yang Y, Ko TP, Chen CC, Huang G, Zheng Y, Liu W, Wang I, Ho MR, Hsu ST, O'Dowd B, Huff HC, Huang CH, Docampo R, Oldfield E, Guo RT. ACS Chem Biol 11 1362-1371 (2016)
  10. Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy. Guan Y, Jiang S, Ye W, Ren X, Wang X, Zhang Y, Yin M, Wang K, Tao Y, Yang J, Cao D, Cheng Y. Cell Death Dis 11 948 (2020)
  11. In Vitro and In Vivo Investigation of the Inhibition of Trypanosoma brucei Cell Growth by Lipophilic Bisphosphonates. Yang G, Zhu W, Kim K, Byun SY, Choi G, Wang K, Cha JS, Cho HS, Oldfield E, No JH. Antimicrob Agents Chemother 59 7530-7539 (2015)
  12. The Antitumor Effect of Lipophilic Bisphosphonate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb. Rittler D, Baranyi M, Molnár E, Garay T, Jalsovszky I, Varga IK, Hegedűs L, Aigner C, Tóvári J, Tímár J, Hegedűs B. Int J Mol Sci 20 E4917 (2019)
  13. A large-scale RNA interference screen identifies genes that regulate autophagy at different stages. Guo S, Pridham KJ, Virbasius CM, He B, Zhang L, Varmark H, Green MR, Sheng Z. Sci Rep 8 2822 (2018)
  14. Combining Vγ9Vδ2 T Cells with a Lipophilic Bisphosphonate Efficiently Kills Activated Hepatic Stellate Cells. Zhou X, Gu Y, Xiao H, Kang N, Xie Y, Zhang G, Shi Y, Hu X, Oldfield E, Zhang X, Zhang Y. Front Immunol 8 1381 (2017)
  15. Head-to-Head Prenyl Synthases in Pathogenic Bacteria. Schwalen CJ, Feng X, Liu W, O-Dowd B, Ko TP, Shin CJ, Guo RT, Mitchell DA, Oldfield E. Chembiochem 18 985-991 (2017)
  16. Targeting RNA helicase DHX33 blocks Ras-driven lung tumorigenesis in vivo. Wang X, Feng W, Peng C, Chen S, Ji H, Zhong H, Ge W, Zhang Y. Cancer Sci 111 3564-3575 (2020)
  17. Development and Validation of a Prognostic Autophagy-Related Gene Pair Index Related to Tumor-Infiltrating Lymphocytes in Early-Stage Lung Adenocarcinoma. Wang ZH, Li Y, Zhang P, Xiang X, Wei XS, Niu YR, Ye LL, Peng WB, Zhang SY, Xue QQ, Zhou Q. Front Cell Dev Biol 9 719011 (2021)
  18. Lipophilic bisphosphonates plus rapamycin: a deadly combination for KRAS-mutated lung adenocarcinoma. Liu W, Zhang T, Guo L, Yang Y. Ann Transl Med 3 289 (2015)
  19. Synergistic binding of actinomycin D and echinomycin to DNA mismatch sites and their combined anti-tumour effects. Satange R, Chang CC, Li LY, Lin SH, Neidle S, Hou MH. Nucleic Acids Res 51 3540-3555 (2023)


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