MIT News breed · Science

Lung Cancers Can Evade KRAS Drugs Through Tissue Transformation

While KRAS inhibitors have been approved for lung cancer treatment, tumors often develop resistance. Researchers have identified a novel resistance mechanism involving a transformation of tumor cell type.

Mutations in the KRAS gene drive uncontrolled cell growth in about 25 percent of lung adenocarcinomas. Although FDA-approved KRAS inhibitors can be effective initially, tumors typically develop resistance over time.

Common resistance mechanisms involve reactivating KRAS through mutations that prevent drug binding or by increasing KRAS expression. However, a new study modeled an alternative resistance pathway.

Researchers found that some lung tumors can transform from adenocarcinoma to squamous cell carcinoma. These two types of tumors originate from different cells and have distinct genetic profiles.

During this transformation, tumor cells appear to no longer require KRAS and activate alternative signaling pathways for continued growth. Identifying these pathways could lead to new drugs to prevent resistance.

The study used a mouse model engineered to express the KRAS mutation targeted by FDA-approved inhibitors. Following treatment, tumors with genetic loss of Nkx2-1 and activation of transcription factors DeltaNp63 or SOX2 underwent adeno-to-squamous transition.

Tumors that transformed did not acquire mutations that typically boost KRAS expression. Instead, KRAS signaling was reduced, suggesting the activation of other growth pathways.

The researchers are investigating the changes in tumor cells during this transition to identify potential drug targets to overcome this resistance mechanism.

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