Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas
Marina Salmón, … , Matthias Drosten, Mariano Barbacid
Marina Salmón, … , Matthias Drosten, Mariano Barbacid
Published March 16, 2023
Citation Information: J Clin Invest. 2023;133(7):e164413. https://doi.org/10.1172/JCI164413.
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Research Article Oncology

Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas

Abstract

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

Authors

Marina Salmón, Ruth Álvarez-Díaz, Coral Fustero-Torre, Oksana Brehey, Carmen G. Lechuga, Manuel Sanclemente, Fernando Fernández-García, Alejandra López-García, María Carmen Martín-Guijarro, Sandra Rodríguez-Perales, Emily Bousquet-Mur, Lucía Morales-Cacho, Francisca Mulero, Fátima Al-Shahrour, Lola Martínez, Orlando Domínguez, Eduardo Caleiras, Sagrario Ortega, Carmen Guerra, Monica Musteanu, Matthias Drosten, Mariano Barbacid

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Figure 6

Tumor response to sotorasib treatment in KG12CP mice.

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Tumor response to sotorasib treatment in KG12CP mice. (A) Waterfall plot...
(A) Waterfall plot representing the changes in tumor volumes of individual lung tumors present in Kras+/FSFG12C;Trp53F/F (KG12CP) mice treated with sotorasib for 1 month (n = 15 mice/52 tumors). Tumors whose volume at the time of the first CT were smaller (orange) or larger (black bars) than 2 mm3 are indicated. (B) Tumor volumes determined by CT scans of representative tumors in KG12CP mice treated with sotorasib for the indicated times. (C) CT scans (top) and 3D rendering (bottom) of lungs of KG12CP mice at the beginning (day 0) and after sotorasib treatment for 4 and 20 weeks (w). Visible lesions are outlined by dotted lines (above) and in red (bottom). (D) Representative images of H&E, Ki67, pERK, cleaved caspase-3 (CC3), and CD8 staining in paraffin-embedded sections of tumors from KG12CP mice either untreated (Control), treated with sotorasib for 1 or 2 weeks, and after they became resistant to sotorasib (Resistant). Scale bars: 20 μm. (E) Quantification of the percentages of Ki67+, CC3+, and CD8+ cells and pERK+ areas in sections of tumors from KG12CP mice either untreated (C) or treated with sotorasib for 1 or 2 weeks, and after they became resistant to sotorasib (R). Data are represented as mean ± SEM. P values were calculated using 1-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001. (F) Percentages of the different histological grades (II to V) displayed by lung tumors in KG12CP mice. Different shades of gray indicate increasing grades. Tumors present in KG12CP mice untreated, treated with sotorasib for 1 or 2 weeks, and after they became resistant to sotorasib are indicated.