Lung cancers can use two different mechanisms to evade KRAS-inhibiting drugs
About 25% of lung adenocarcinomas have mutations of the gene KRAS, which drives uncontrolled cell growth. In recent years, the FDA has approved two KRAS inhibitors to treat patients with KRAS mutations. While these drugs can work well initially, tumors almost always develop resistance to them.
About 25% of lung adenocarcinomas have KRAS gene mutations that drive uncontrolled cell growth. Two KRAS inhibitors approved by the FDA treat these patients, but tumors usually become resistant over time. Resistance can result from cells reactivating KRAS activity or increasing KRAS expression. However, a new study reveals an alternative mechanism where lung tumors transform from adenocarcinoma to squamous cell carcinoma, a process that no longer requires KRAS and activates different signaling pathways for continued growth.
Researchers at MIT found that this transition occurs when tumors lose a gene called Nkx2-1, which maintains alveolar epithelial identity. Other transcription factors like DeltaNp63 and SOX2 also contribute to this transformation. When tumors undergo this tissue change, they no longer express mutations that boost KRAS expression and instead shut down KRAS signaling.
Identifying the pathways these resistant squamous tumors rely on could lead to new drug targets to counteract KRAS inhibitor resistance.
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