The CRISPR-Cas9 Mediated KRAS Mutation Targeting: Overcoming Immune Evasion in Lung Cancer
The CRISPR-Cas9 Mediated KRAS Mutation Targeting: Overcoming Immune Evasion in Lung Cancer
Sohaib Najafi,1Faramarz Khosravi,2,*
1. Bachelor’s student, Microbiology group, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran 2. Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Introduction: Lung carcinoma continues to be a predominant contributor to cancer-associated mortality on a global scale, with non-small cell lung carcinoma (NSCLC) representing the most widespread subtype. A considerable obstacle in the therapeutic management of NSCLC is the existence of KRAS mutations, notably the KRAS^G12C variant. Recent progress in CRISPR-Cas9 technology has facilitated novel strategies for targeting these mutations, thereby providing optimism for the potential to surmount immune evasion mechanisms in lung carcinoma.
Methods: Researchers engaged in an innovative exploration utilizing in vivo CRISPR-Cas9 screening
methodologies. They developed a bespoke library aimed at 240 genes modulated by KRAS.
This pioneering investigation was conducted within a murine model of KRAS-mutant lung
cancer. Subsequently, they introduced the genetically modified cells into mice to assess the
resultant impact on immune responses. Sequencing of the genomic DNA extracted from tumors
facilitated the identification of active sgRNAs and revealed the underlying mechanisms
contributing to immune evasion.
Results: The investigation revealed a critical observation: KRAS mutations significantly elevate COX2 expression, which consequently enhances the synthesis of prostaglandin E2 (PGE2), a bioactive molecule that inhibits immune function. This PGE2 pathway emerged as a central determinant in the resistance to immune checkpoint blockade (ICB) therapies, particularly those targeting PD1. The PGE2 compound fosters a tumor microenvironment that diminishes cytotoxic T-cell efficacy while facilitating the rise of myeloid-derived suppressor cells.
Nonetheless, by targeting the COX2/PGE2 axis, researchers accomplished remarkable outcomes. The tumor microenvironment was successfully reengineered, creating a proinflammatory atmosphere in myeloid cells, which thereby facilitated the infiltration and activation of CD8+ T-cells. This transformation markedly improved the efficacy of ICB therapies in KRAS-mutant lung tumors, resulting in more robust antitumor immune responses. Furthermore, the inhibition of COX2 postponed tumor recurrence subsequent to the targeting of KRASG12C, suggesting a potent synergistic interaction between these therapeutic modalities.
Conversely, the study also indicated that the reinstatement of COX2 expression precipitated tumor relapse following extended KRAS inhibition. This observation implies that persistent COX2 activity may compromise the long-term efficacy of KRAS-targeted therapies, thereby underscoring the necessity for concurrent COX2 inhibition.
Conclusion: This research highlights the complex mechanisms through which KRAS mutations facilitate immune evasion in lung cancer. The research highlights COX2's role as a key player in the challenges faced with immunotherapy, paving the way for combining COX2/PGE2 pathway blockers with therapies aimed at KRAS. This combinatorial strategy presents significant potential for overcoming resistance and enhancing treatment outcomes for patients afflicted with KRAS-mutant lung cancer. Future investigations should focus on refining these combination therapies and examining the broader implications of targeting immune evasion in oncological treatments.