Drug sensitivity profile of minor KRAS mutations in colorectal cancer using mix culture assay: The effect of AMG‑510, a novel KRAS G12C selective inhibitor, on colon cancer cells is markedly enhanced by the combined inhibition of MEK and BCL‑XL

Kitazawa,Masato; Miyagawa,Yusuke; Koyama,Makoto; Nakamura,Satoshi; Hondo,Nao; Miyazaki,Satoru; Muranaka,Futoshi; Tokumaru,Shigeo; Yamamoto,Yuta; Ehara,Takehito; Kuroiwa,Masatsugu; Tanaka,Hirokazu; Komatsu,Daisuke; Takeoka,Michiko; Soejima,Yuji

doi:10.3892/mco.2021.2310

Drug sensitivity profile of minor KRAS mutations in colorectal cancer using mix culture assay: The effect of AMG‑510, a novel KRAS G12C selective inhibitor, on colon cancer cells is markedly enhanced by the combined inhibition of MEK and BCL‑XL

Authors:
- Masato Kitazawa
- Yusuke Miyagawa
- Makoto Koyama
- Satoshi Nakamura
- Nao Hondo
- Satoru Miyazaki
- Futoshi Muranaka
- Shigeo Tokumaru
- Yuta Yamamoto
- Takehito Ehara
- Masatsugu Kuroiwa
- Hirokazu Tanaka
- Daisuke Komatsu
- Michiko Takeoka
- Yuji Soejima
View Affiliations

Affiliations: Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390‑8621, Japan, Department of Surgery, Jinai Hospital, Ina, Nagano 396‑0026, Japan
Published online on: May 28, 2021 https://doi.org/10.3892/mco.2021.2310
Article Number: 148
Copyright: © Kitazawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Colorectal cancer with a Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) gene mutation is considered to be resistant to anti‑EGFR agents. G12D is the most common KRAS mutation in colorectal cancer, followed by G12V and G13D. According to clinical and basic research data, patients with colorectal cancer exhibiting G12D and G12V KRAS mutations are resistant to anti‑EGFR agents; however, this is not true of G13D and other minor mutations, which are still not well understood. The current study focused on minor KRAS mutations (G12A, G12C, G12S, Q61H and A146T) and evaluated whether these were resistant to anti‑EGFR antibodies using a mix culture assay. The results demonstrated that all KRAS mutations, including minor mutations, were resistant to two anti‑EGFR agents: Cetuximab and panitumumab. The combined effect of MEK and BCL‑XL inhibition on colorectal cancer cells with KRAS minor mutations were subsequently evaluated. The combined effect of MEK and BCL‑XL inhibitors was confirmed in all KRAS minor mutations. The sensitivity of AMG510, a novel KRAS G12C selective inhibitor, was also assessed. The mix culture assay revealed that AMG510 selectively exerted an antitumor effect on colon cancer cells with a G12C KRAS mutation. The combination of MEK and BCL‑XL inhibition markedly enhanced the effect of AMG510 in colon cancer cells. The current study suggested that AMG510 may have potential clinical use in combination with MEK and BCL‑XL inhibitors in the treatment of patients with colorectal cancer exhibiting the G12C KRAS mutation.

View Figures

View References

1	Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, et al: K-ras Mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 359:1757–1765. 2008.PubMed/NCBI View Article : Google Scholar
2	Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 26:1626–1634. 2008.PubMed/NCBI View Article : Google Scholar
3	Imamura Y, Lochhead P, Yamauchi M, Kuchiba A, Qian ZR, Liao X, Nishihara R, Jung S, Wu K, Nosho K, et al: Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review. Mol Cancer. 13(135)2014.PubMed/NCBI View Article : Google Scholar
4	Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66:3992–3995. 2006.PubMed/NCBI View Article : Google Scholar
5	Dahabreh IJ, Terasawa T, Castaldi PJ and Trikalinos TA: Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 154:37–49. 2011.PubMed/NCBI View Article : Google Scholar
6	De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, et al: Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 304:1812–1820. 2010.PubMed/NCBI View Article : Google Scholar
7	Kumar SS, Price TJ, Mohyieldin O, Borg M, Townsend A and Hardingham JE: KRAS G13D mutation and sensitivity to cetuximab or panitumumab in a colorectal cancer cell line model. Gastrointest Cancer Res. 7:23–26. 2014.PubMed/NCBI
8	Kitazawa M, Hida S, Fujii C, Taniguchi S, Ito K, Matsumura T, Okada N, Sakaizawa T, Kobayashi A, Takeoka M and Miyagawa SI: ASC induces apoptosis via activation of caspase-9 by enhancing Gap junction-mediated intercellular communication. PLoS One. 12(e0169340)2017.PubMed/NCBI View Article : Google Scholar
9	Koyama M, Kitazawa M, Nakamura S, Matsumura T, Miyazaki S, Miyagawa Y, Muranaka F, Tokumaru S, Okumura M, Yamamoto Y, et al: Low-dose trametinib and Bcl-xl antagonist have a specific antitumor effect in KRAS-mutated colorectal cancer cells. Int J Oncol. 57:1179–1191. 2020.PubMed/NCBI View Article : Google Scholar
10	AACR Project GENIE Consortium. AACR Project GENIE: Powering precision medicine through an International Consortium. Cancer Discov. 7:818–831. 2017.PubMed/NCBI View Article : Google Scholar
11	Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF and Uzzan B: Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 45:1890–1896. 2009.PubMed/NCBI
12	Poulikakos PI, Zhang C, Bollag G, Shokat KM and Rosen N: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 464:427–430. 2010.PubMed/NCBI View Article : Google Scholar
13	Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A and Bernards R: Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 483:100–103. 2012.PubMed/NCBI View Article : Google Scholar
14	Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, et al: Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 14:1351–1356. 2008.PubMed/NCBI View Article : Google Scholar
15	Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, Lifshits E, Ryan DP, Meyerhardt JA, Benes C, Settleman J, et al: Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest. 121:4311–4321. 2011.PubMed/NCBI View Article : Google Scholar
16	Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM and Engelman JA: MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 72:3228–3237. 2012.PubMed/NCBI View Article : Google Scholar
17	Manchado E, Weissmueller S, Morris JP IV, Chen CC, Wullenkord R, Lujambio A, de Stanchina E, Poirier JT, Gainor JF, Corcoran RB, et al: A Combinatorial strategy for treating KRAS-mutant lung cancer. Nature. 534:647–651. 2016.PubMed/NCBI View Article : Google Scholar
18	Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, Asthana S, Neel D, Yan JJ, Lu X, et al: The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet. 47:250–256. 2015.PubMed/NCBI View Article : Google Scholar
19	Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, et al: Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell. 23:121–128. 2013.PubMed/NCBI View Article : Google Scholar
20	Ziemke EK, Dosch JS, Maust JD, Shettigar A, Sen A, Welling TH, Hardiman KM and Sebolt-Leopold JS: Sensitivity of KRAS-mutant colorectal cancers to combination therapy that cotargets MEK and CDK4/6. Clin Cancer Res. 22:405–414. 2016.PubMed/NCBI View Article : Google Scholar
21	Tao Z, Le Blanc JM, Wang C, Zhan T, Zhuang H, Wang P, Yuan Z and Lu B: Coadministration of Trametinib and Palbociclib radiosensitizes KRAS-mutant non-small cell lung cancers in vitro and in vivo. Clin Cancer Res. 22:122–133. 2016.PubMed/NCBI View Article : Google Scholar
22	Lee MS, Helms TL, Feng N, Gay J, Chang QE, Tian F, Wu JY, Toniatti C, Heffernan TP, Powis G, et al: Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models. Oncotarget. 7:39595–39608. 2016.PubMed/NCBI View Article : Google Scholar
23	Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, Hong CB and Corcoran RB: Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS G12C inhibition. Clin Cancer Res. 26:1633–1643. 2020.PubMed/NCBI View Article : Google Scholar