132
Views
0
CrossRef citations to date
0
Altmetric
Special Report

Deterministic reprogramming and signaling activation following targeted therapy in non-small cell lung cancer driven by mutations or oncogenic fusions

, , , &
Pages 171-182 | Received 27 Nov 2023, Accepted 15 Feb 2024, Published online: 23 Feb 2024

References

  • Rosell R, Karachaliou N. Large-scale screening for somatic mutations in lung cancer. Lancet. 2016 Apr 2;387(10026):1354–1356. doi: 10.1016/S0140-6736(15)01125-3
  • Hendriks LE, Kerr KM, Menis J, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Apr;34(4):339–357.
  • Kästner A, Kron A, van den Berg N, et al. Evaluation of the effectiveness of a nationwide precision medicine program for patients with advanced non-small cell lung cancer in Germany: a historical cohort analysis. Lancet Reg Health Eur. 2024 Jan;36:100788.
  • Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a Consensus Statement from the International Association for the study of lung cancer. J Thorac Oncol. 2021 Oct;16(10):1647–1662.
  • Rosell R, Santarpia M, Pedraz-Valdunciel C, et al. Liquid biopsy in detecting early non-small cell lung cancer. J Liquid Biopsy. 2023;1:100001. doi: 10.1016/j.jlb.2023.100001
  • Lee JM, McNamee CJ, Toloza E, et al. Neoadjuvant targeted therapy in Resectable NSCLC: Current and future perspectives. J Thorac Oncol. 2023 Nov;18(11):1458–1477.
  • Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-Mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113–125. doi: 10.1056/NEJMoa1713137
  • Choudhury NJ, Marra A, Sui JSY, et al. Molecular biomarkers of disease outcomes and mechanisms of acquired resistance to first-line osimertinib in advanced EGFR-Mutant lung cancers. J Thorac Oncol. 2023 Apr;18(4):463–475.
  • Lara-Mejía L, Cardona AF, Mas L, et al. Impact of concurrent genomic alterations on clinical outcomes in patients with ALK-Rearranged NSCLC. J Thorac Oncol. 2023 Aug 10;19(1):119–129. doi: 10.1016/j.jtho.2023.08.007
  • Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-targterations as early resistance mechanisms to First-line Osimertinib in EGFR-Mutant lung cancer. Clin Cancer Res. 2020 Jun 1;26(11):2654–2663.
  • Nagasaka M, Zhu VW, Lim SM, et al. Beyond osimertinib: the development of third-generation EGFR tyrosine kinase inhibitors for advanced EGFR+ NSCLC. J Thorac Oncol. 2021 May;16(5):740–763.
  • Cooper AJ, Sequist LV, Lin JJ. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol. 2022 Aug;19(8):499–514. doi: 10.1038/s41571-022-00639-9
  • Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non–small-Cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387(2):120–131. doi: 10.1056/NEJMoa2204619
  • Xie X, Yu T, Li X, et al. Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials. Signal Transduct Target Ther. 2023 Sep 6;8(1):335. doi: 10.1038/s41392-023-01589-z
  • Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021 Jun 24;384(25):2371–2381. doi: 10.1056/NEJMoa2103695
  • Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation. N Engl J Med. 2022 Jul 14;387(2):120–131. doi: 10.1056/NEJMoa2204619
  • Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. 2023 Aug 24;389(8):710–721. doi: 10.1056/NEJMoa2303810
  • Salmón M, Álvarez-Díaz R, Fustero-Torre C. et al. Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas. J Clin Invest. 2023 Apr 3;133(7). doi: 10.1172/JCI164413
  • Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-Rearranged lung cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316
  • Tani T, Yasuda H, Hamamoto J, et al. Activation of EGFR bypass signaling by TGFα overexpression induces acquired resistance to alectinib in ALK-Translocated lung cancer cells. Mol Cancer Ther. 2016 Jan;15(1):162–171.
  • Yamada T, Takeuchi S, Nakade J, et al. Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. Clin Cancer Res. 2012 Jul 1;18(13):3592–3602. doi: 10.1158/1078-0432.CCR-11-2972
  • Lovly CM, McDonald NT, Chen H, et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer. Nature Med. 2014;20(9):1027–1034. doi: 10.1038/nm.3667
  • Crystal AS, Shaw AT, Sequist LV, et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science. 2014 Dec 19;346(6216):1480–1486. doi: 10.1126/science.1254721
  • Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012 Mar 1;18(5):1472–1482. doi: 10.1158/1078-0432.CCR-11-2906
  • Dagogo-Jack I, Yoda S, Lennerz JK, et al. MET aterations are a recurring and actionable resistance mechanism in ALK-Positive lung cancer. Clin Cancer Res. 2020 Jun 1;26(11):2535–2545. doi: 10.1158/1078-0432.CCR-19-3906
  • Rosen EY, Johnson ML, Clifford SE, et al. Overcoming MET-Dependent resistance to selective RET inhibition in patients with RET fusion-positive lung cancer by combining selpercatinib with Crizotinib. Clin Cancer Res. 2021 Jan 1;27(1):34–42. doi: 10.1158/1078-0432.CCR-20-2278
  • Coleman N, Hong L, Zhang J, et al. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2021 Dec;6(6):100319.
  • Chaib I, Karachaliou N, Pilotto S. et al. Co-activation of STAT3 and YES-Associated protein 1 (YAP1) pathway in EGFR-Mutant NSCLC. J Natl Cancer Inst. 2017 Sep 1;109(9). doi: 10.1093/jnci/djx014
  • Sordella R, Bell DW, Haber DA, et al. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004 Aug 20;305(5687):1163–1167. doi: 10.1126/science.1101637
  • Schneider JL, Lin JJ, Shaw AT. ALK-positive lung cancer: a moving target. Nat Cancer. 2023 Mar;4(3):330–343. doi: 10.1038/s43018-023-00515-0
  • Zhu T, Xie J, He H, et al. Phase separation underlies signaling activation of oncogenic NTRK fusions. Proc Natl Acad Sci U S A. 2023 Oct 17;120(42):e2219589120. doi: 10.1073/pnas.2219589120
  • Neel DS, Allegakoen DV, Olivas V, et al. Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins. Cancer Res. 2019 Feb 1;79(3):546–556. doi: 10.1158/0008-5472.CAN-18-1492
  • Michels S, Massutí B, Schildhaus HU, et al. Safety and efficacy of Crizotinib in patients with advanced or Metastatic ROS1-Rearranged lung cancer (EUCROSS): a European Phase II Clinical Trial. J Thorac Oncol. 2019 Jul;14(7):1266–1276.
  • Giménez-Capitán A, Sánchez-Herrero E, Robado de Lope L, et al. Detecting ALK, ROS1, and RET fusions and the METΔex14 splicing variant in liquid biopsies of non-small-cell lung cancer patients using RNA-based techniques. Mol Oncol. 2023 Sep;17(9):1884–1897.
  • Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963–1971. doi: 10.1056/NEJMoa1406766
  • Drilon A, Camidge DR, Lin JJ, et al. Repotrectinib in ROS1 Fusion–positive non–small-Cell lung cancer. N Engl J Med. 2024;390(2):118–131. doi: 10.1056/NEJMoa2302299
  • Lin JJ, Choudhury NJ, Yoda S, et al. Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 Fusion-Positive lung cancer. Clin Cancer Res. 2021 May 15;27(10):2899–2909. doi: 10.1158/1078-0432.CCR-21-0032
  • Liu D, Flory J, Lin A, et al. Characterization of on-target adverse events caused by TRK inhibitor therapy. Ann Oncol. 2020 Sep;31(9):1207–1215.
  • Drilon A, Horan JC, Tangpeerachaikul A, et al. NVL-520 is a selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 fusions and secondary resistance mutations. Cancer Discov. 2023 Mar 1;13(3):598–615. doi: 10.1158/2159-8290.CD-22-0968
  • Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012 Feb 12;18(3):378–381. doi: 10.1038/nm.2658
  • Sabir SR, Yeoh S, Jackson G, et al. EML4-ALK variants: biological and molecular properties, and the implications for patients. Cancers (Basel). 2017 Sep 5;9(9):118. doi: 10.3390/cancers9090118
  • Hrustanovic G, Olivas V, Pazarentzos E, et al. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med. 2015 Sep;21(9):1038–1047.
  • Richards MW, Law EW, Rennalls LP, et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5195–5200. doi: 10.1073/pnas.1322892111
  • Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693–1703. doi: 10.1056/NEJMoa1006448
  • Tulpule A, Guan J, Neel DS, et al. Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules. Cell. 2021 May 13;184(10):2649–2664.e18. doi: 10.1016/j.cell.2021.03.031
  • Sampson J, Richards MW, Choi J, et al. Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation. EMBO Rep. 2021 Dec 6;22(12):e53693. doi: 10.15252/embr.202153693
  • Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385–2894. doi: 10.1056/NEJMoa1214886
  • Chen Z, Akbay E, Mikse O, et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res. 2014 Mar 1;20(5):1204–1211. doi: 10.1158/1078-0432.CCR-13-1733
  • Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014 Dec 4;371(23):2167–2177. doi: 10.1056/NEJMoa1408440
  • Solomon BJ, Kim DW, Wu YL, et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-Mutation-Positive Non-Small-Cell lung cancer. J Clin Oncol. 2018 Aug 1;36(22):2251–2258. doi: 10.1200/JCO.2017.77.4794
  • Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in untreated ALK-Positive non-small-cell lung cancer. N Engl J Med. 2017 Aug 31;377(9):829–838. doi: 10.1056/NEJMoa1704795
  • Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and Safety Data and impact of the EML4-ALK Fusion Variant on the efficacy of Alectinib in untreated ALK-Positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol. 2019 Jul;14(7):1233–1243.
  • Christopoulos P, Endris V, Bozorgmehr F, et al. EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK(+) non-small cell lung cancer. Int J Cancer. 2018 Jun 15;142(12):2589–2598. doi: 10.1002/ijc.31275
  • Li J, Huang K, Ji H, et al. Efficacy of alectinib in lung adenocarcinoma patients with different anaplastic lymphoma kinase (ALK) rearrangements and co-existing alterations-a retrospective cohort study. Transl Lung Cancer Res. 2023 Dec 26;12(12):2505–2519. doi: 10.21037/tlcr-23-658
  • Zhou C, Kim SW, Reungwetwattana T, et al. Alectinib versus crizotinib in untreated Asian patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer (ALESIA): a randomised phase 3 study. Lancet Respir Med. 2019 May;7(5):437–446.
  • Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29–39. doi: 10.1016/S0140-6736(17)30565-2
  • Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-Positive lung cancer. N Engl J Med. 2020 Nov 19;383(21):2018–2029. doi: 10.1056/NEJMoa2027187
  • Solomon BJ, Bauer TM, Mok TSK, et al. Efficacy and safety of first-line lorlatinib versus crizotinib in patients with advanced, ALK-positive non-small-cell lung cancer: updated analysis of data from the phase 3, randomised, open-label CROWN study. Lancet Respir Med. 2023 Apr;11(4):354–366.
  • Bearz A, Martini J-F, Jassem J, et al. Efficacy of lorlatinib in treatment-naive patients with ALK-Positive advanced NSCLC in relation to EML4: ALK variant type and ALK with or without TP53 mutations. J Thorac Oncol. 2023;18(11):1581–1593. doi: 10.1016/j.jtho.2023.07.023
  • Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-Positive NSCLC: final results of phase 3 ALTA-1L trial. J Thorac Oncol. 2021 Dec;16(12):2091–2108.
  • Qin Z, Sun H, Yue M, et al. Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis. Cell Discov. 2021 May 11;7(1):33. doi: 10.1038/s41421-021-00270-5
  • Alberti S, Gladfelter A, Mittag T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell. 2019 Jan 24;176(3):419–434. doi: 10.1016/j.cell.2018.12.035
  • Mehta S, Zhang J. Liquid-liquid phase separation drives cellular function and dysfunction in cancer. Nat Rev Cancer. 2022 Apr;22(4):239–252. doi: 10.1038/s41568-022-00444-7
  • Xie J, He H, Kong W, et al. Targeting androgen receptor phase separation to overcome antiandrogen resistance. Nat Chem Biol. 2022;18(12):1341–1350. doi: 10.1038/s41589-022-01151-y
  • Zhu G, Xie J, Kong W, et al. Phase separation of disease-associated SHP2 mutants underlies MAPK hyperactivation. Cell. 2020 Oct 15;183(2):490–502.e18. doi: 10.1016/j.cell.2020.09.002
  • Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001 May 17;411(6835):355–365. doi: 10.1038/35077225
  • Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nature Med. 2012;18(3):375–377. doi: 10.1038/nm.2644
  • Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012 Feb 12;18(3):382–384. doi: 10.1038/nm.2673
  • Zhou C, Solomon B, Loong HH, et al. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion–positive NSCLC. N Engl J Med. 2023 Oct 21;389(20):1839–1850. doi: 10.1056/NEJMoa2309457
  • Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018 Mar;15(3):151–167.
  • Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET Fusion-Positive Non-Small-Cell lung cancer. N Engl J Med. 2020 Aug 27;383(9):813–824. doi: 10.1056/NEJMoa2005653
  • Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021 Jul;22(7):959–969.
  • Miyazaki I, Odintsov I, Ishida K, et al. Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations. Nat Cancer. 2023;4(9):1345–1361. doi: 10.1038/s43018-023-00630-y
  • Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nature Med. 2013;19(11):1469–1472. doi: 10.1038/nm.3352
  • Amatu A, Sartore-Bianchi A, Bencardino K, et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol. 2019 Nov 1;30(Suppl_8):viii5–viii15. doi: 10.1093/annonc/mdz383
  • Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020 Apr;21(4):531–540.
  • Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb;21(2):271–282.
  • Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Nov;575(7781):217–223.
  • Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discovery. 2018;8(7):822–835. doi: 10.1158/2159-8290.CD-18-0099
  • Ricciuti B, Son J, Okoro JJ, et al. Comparative analysis and Isoform-Specific Therapeutic Vulnerabilities of KRAS mutations in non-small cell lung cancer. Clin Cancer Res. 2022 Apr 14;28(8):1640–1650. doi: 10.1158/1078-0432.CCR-21-2719
  • Pavan A, Bragadin AB, Calvetti L, et al. Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome. Transl Lung Cancer Res. 2021 Jan;10(1):202–220.
  • Kitajima S, Ivanova E, Guo S, et al. Suppression of STING associated with LKB1 loss in KRAS-Driven lung cancer. Cancer Discov. 2019 Jan;9(1):34–45.
  • Santarpia M, Aguilar A, Chaib I, et al. Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies. Cancers (Basel). 2020 Jun 5;12(6):1475. doi: 10.3390/cancers12061475
  • Yoda S, Lin JJ, Lawrence MS, et al. Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-Positive lung cancer. Cancer Discov. 2018 Jun;8(6):714–729.
  • Shaw AT, Solomon BJ, Besse B, et al. ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol. 2019 Jun 1;37(16):1370–1379. doi: 10.1200/JCO.18.02236
  • Rosell R, Cardona AF, Arrieta O, et al. Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities. Br J Cancer. 2021;125(12):1602–1611. doi: 10.1038/s41416-021-01519-2
  • Karachaliou N, Chaib I, Cardona AF, et al. Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive non-small cell lung cancer associated with poor prognosis. EBioMedicine. 2018 Mar;29:112–127.
  • Kurppa KJ, Liu Y, To C, et al. Treatment-Induced tumor Dormancy through YAP-Mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell. 2020 Jan 13;37(1):104–122.e12. doi: 10.1016/j.ccell.2019.12.006
  • Nilsson MB, Sun H, Robichaux J. et al. A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components. Sci Transl Med. 2020 Sep 2;12(559). doi: 10.1126/scitranslmed.aaz4589
  • Yun MR, Choi HM, Lee YW, et al. Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer. EMBO Mol Med. 2019;11(12):e10581. doi: 10.15252/emmm.201910581
  • Tsuji T, Ozasa H, Aoki W, et al. YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation. Nat Commun. 2020;11(1):74. doi: 10.1038/s41467-019-13771-5
  • Wang L, Choi K, Su T, et al. Multiphase coalescence mediates Hippo pathway activation. Cell. 2022 Nov 10;185(23):4376–4393.e18. doi: 10.1016/j.cell.2022.09.036
  • Franklin JM, Wu Z, Guan KL. Insights into recent findings and clinical application of YAP and TAZ in cancer. Nat Rev Cancer. 2023 Aug;23(8):512–525. doi: 10.1038/s41568-023-00579-1
  • Adachi Y, Kimura R, Hirade K, et al. Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS. Nat Cancer. 2023 Jun;4(6):829–843.
  • Hagenbeek TJ, Zbieg JR, Hafner M, et al. An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance. Nat Cancer. 2023 Jun;4(6):812–828.
  • Kwon JJ, Hajian B, Bian Y, et al. Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. Nature. 2022 Sep;609(7926):408–415.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.