Anticancer drug discovery has yielded unprecedented progress in recent decades, resulting in the approval of innovative treatment options for patients and the successful implementation of personalized medicine in clinical practice. This remarkable progress has also reshaped the research scope of pharmacological research. This article, as a tribute to cancer research at Shanghai Institute of Materia Medica in celebration of the institute’s 90th birthday, provides an overview of the conceptual revolution occurring in anticancer therapy, and summarizes our recent progress in the development of molecularly targeted therapeutics and exploration of new strategies in personalized medicine. With this review, we hope to provide a glimpse into how antitumor pharmacological researchers have embraced the new era of personalized medicine research and to propose a future path for anticancer drug discovery and pharmacological research.
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Huang M, Shen A, Ding J, Geng M. Molecularly targeted cancer therapy: some lessons from the past decade. Trends Pharmacol Sci. 2014;35:41–50.
de Jonge MJ, Verweij J. Multiple targeted tyrosine kinase inhibition in the clinic: all for one or one for all? Eur J Cancer. 2006;42:1351–6.
Faivre S, Djelloul S, Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol. 2006;33:407–20.
Weinstein IB. Cancer. Addiction to oncogenes–the Achilles heal of cancer. Science. 2002;297:63–4.
Cohen P, Cross D, Janne PA. Kinase drug discovery 20 years after imatinib: progress and future directions. Nat Rev Drug Discov. 2021;20:551–69.
Paliouras S, Pearson A, Barkalow F. The most successful oncology drug portfolios of the past decade. Nat Rev Drug Discov. 2021;20:811–2.
Torti D, Trusolino L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med. 2011;3:623–36.
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378:2386–98.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.
Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383:1207–17.
Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217–23.
Herbst RS, Schlessinger J. Small molecule combats cancer-causing KRAS protein at last. Nature. 2019;575:294–5.
Miao ZH, Feng JM, Ding J. Newly discovered angiogenesis inhibitors and their mechanisms of action. Acta Pharmacol Sin. 2012;33:1103–11.
Dienstmann R, Andre F, Soria JC. Significant antitumor activity of E-3810, a novel FGFR and VEGFR inhibitor, in patients with FGFR1 amplified breast cancer. 2012 ESMO Congress 2012; Abstract 3190: Presented October 1, 2012.
Zhou Y, Chen Y, Tong L, Xie H, Wen W, Zhang J, et al. AL3810, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR, FGFR and PDGFR. J Cell Mol Med. 2012;16:2321–30.
Zhang Y, Luo F, Ma YX, Liu QW, Yang YP, Fang WF, et al. A phase Ib study of lucitanib (AL3810) in a cohort of patients with recurrent and metastatic nasopharyngeal carcinoma. Oncologist. 2022;27:e453–62.
Ai J, Chen Y, Peng X, Ji Y, Xi Y, Shen Y, et al. Preclinical evaluation of SCC244 (glumetinib), a novel, potent, and highly selective inhibitor of c-Met in MET-dependent cancer models. Mol Cancer Ther. 2018;17:751–62.
Lu S, Yu Y, Zhou J, Goto K, Li X, Sakakibara-Konishi J, et al. Abstract CT034: phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study). Cancer Res. 2022;82(Suppl 12):CT034.
Xiang HY, Wang X, Chen YH, Zhang X, Tan C, Wang Y, et al. Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors. Eur J Med Chem. 2021;209:112913.
Wei XL, Xu RH, Zhao H, Zhang Y, Zou BY, Wang F, et al. A first-in-human phase I study of CYH33, a phosphatidylinositol 3-kinase (PI3K) α selective inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2020;38(15_Supplement):e15645.
Zhang T, Qu R, Chan S, Lai M, Tong L, Feng F, et al. Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance. Mol Cancer. 2020;19:90.
Shi Y, Li B, Wu L, Pan Y, Pan Z, Liu Y, et al. Efficacy and safety of limertinib (ASK120067) in patients with locally advanced or metastatic EGFR Thr790Met-mutated NSCLC: a multicenter, single-arm, phase 2b study. J Thorac Oncol. 2022;17:1205–15.
Xia ZJ, Ji YC, Sun DQ, Peng X, Gao YL, Fang YF, et al. SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors. Acta Pharmacol Sin. 2021;42:998–1004.
Chen XX, Shen QQ, Zhao Z, Fang YF, Yang JY, Gao YL, et al. Abstract 5436: HH2853 is a selective small molecular dual inhibitor of EZH1/2 with potent anti-tumor activities. Cancer Res. 2022;82(12_Supplement):5436.
Wang X, Chen Z, Xu J, Tang S, An N, Jiang L, et al. SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors. Cell Res. 2022;32:638–58.
Beckman RA, Clark J, Chen C. Integrating predictive biomarkers and classifiers into oncology clinical development programmes. Nat Rev Drug Discov. 2011;10:735–48.
Kelloff GJ, Sigman CC. Cancer biomarkers: selecting the right drug for the right patient. Nat Rev Drug Discov. 2012;11:201–14.
Shen A, Wang L, Huang M, Sun J, Chen Y, Shen YY, et al. c-Myc alterations confer therapeutic response and acquired resistance to c-Met inhibitors in MET-addicted cancers. Cancer Res. 2015;75:4548–59.
Liu H, Ai J, Shen A, Chen Y, Wang X, Peng X, et al. c-Myc alteration determines the therapeutic response to FGFR inhibitors. Clin Cancer Res. 2017;23:974–84.
Jiang Y, Zeng Q, Jiang Q, Peng X, Gao J, Wan H, et al. (18)F-FDG PET as an imaging biomarker for the response to FGFR-targeted therapy of cancer cells via FGFR-initiated mTOR/HK2 axis. Theranostics. 2022;12:6395–408.
Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell. 2009;136:823–37.
Francies HE, McDermott U, Garnett MJ. Genomics-guided pre-clinical development of cancer therapies. Nat Cancer. 2020;1:482–92.
Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise. Nat Rev Clin Oncol. 2020;17:91–107.
Zeng H, Qu J, Jin N, Xu J, Lin C, Chen Y, et al. Feedback activation of leukemia inhibitory factor receptor limits response to histone deacetylase inhibitors in breast cancer. Cancer Cell. 2016;30:459–73.
Huang X, Yan J, Zhang M, Wang Y, Chen Y, Fu X, et al. Targeting epigenetic crosstalk as a therapeutic strategy for EZH2-aberrant solid tumors. Cell. 2018;175:186–99.e19.
Xie Q, Chi S, Fang Y, Sun Y, Meng L, Ding J, et al. PI3Kalpha inhibitor impairs AKT phosphorylation and synergizes with novel angiogenesis inhibitor AL3810 in human hepatocellular carcinoma. Signal Transduct Target Ther. 2021;6:130.
Xing H, Gao M, Wang Y, Zhang X, Shi J, Wang X, et al. Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3Kalpha inhibitors in oesophageal squamous cell carcinoma. Clin Transl Med. 2022;12:e835.
Wang Y, Li X, Liu X, Chen Y, Yang C, Tan C, et al. Simultaneous inhibition of PI3Kalpha and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer. Cancer Biol Med. 2019;16:66–83.
Sun P, Zhang X, Wang RJ, Ma QY, Xu L, Wang Y, et al. PI3Kalpha inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8+ T cells and promoting fatty acid metabolism. J Immunother Cancer. 2021;9:e003093.
Qu J, Sun W, Zhong J, Lv H, Zhu M, Xu J, et al. Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells. J Cell Biol. 2017;216:409–24.
Liu Z, Liu Y, Qian L, Jiang S, Gai X, Ye S, et al. A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies. Mol Cell. 2021;81:4076–90.e8.
de Miguel M, Calvo E. Clinical challenges of immune checkpoint inhibitors. Cancer Cell. 2020;38:326–33.
Galluzzi L, Humeau J, Buque A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17:725–41.
Lian Q, Xu J, Yan S, Huang M, Ding H, Sun X, et al. Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation. Cell Res. 2017;27:784–800.
The authors sincerely thank all the individuals who have contributed to the work that has been reviewed in this article, including all the members who were either directly or indirectly involved in the Division of Antitumor Pharmacology at SIMM, as well as all our collaborators. This work is supported by the National Natural Science Foundation of China for Innovation Research Group (No. 81821005).
M.H. was a consultant of Haihe Biopharma and J.D. is the Chairman of Board of Haihe Biopharma.
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Huang, M., Geng, My. & Ding, J. Antitumor pharmacological research in the era of personalized medicine. Acta Pharmacol Sin 43, 3015–3020 (2022). https://doi.org/10.1038/s41401-022-01023-0
- personalized medicine
- anticancer drug discovery
- oncogene addiction
- non-oncogene addiction
- combination therapy
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