Authors:

Alisa Gulyansky

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About Paper:

Rat sarcoma proteins (RAS) are a family of small proteins that are often key mediators for cell signaling mechanisms, acting as a light switch with "on" and "off" states. When mutations cause a RAS protein to constitutively stay "on", uncontrolled cell growth occurs leading to cancer. Traditionally, RAS proteins have been considered undruggable, however, recent advances in medicinal chemistry have allowed for the development of multi-RAS(ON) inhibitors, which targets active RAS isoforms. However, the rapid emergence of drug resistance remains a significant barrier in NRAS- mutant melanoma, a subtype of skin cancer characterized by poor clinical outcomes and limited treatment options. Thus, uncovering the molecular and immunologic underpinnings of adaptive resistance in vivo can lead to better clinical strategies. Here, we evaluated the therapeutic response of four NRAS-mutant OSUMMER melanoma cell lines with differing genetic profiles in immunocompetent mice treated with RMC-7977. Tumor growth revealed heterogeneous resistance patterns, with OSUMMER13 maintaining prolonged sensitivity, while OSUMMER1, OSUMMER5, and OSUMMER10 exhibited adaptive regrowth. Western blot analyses showed that RMC-7977- treated tumors variably retained MAPK and PI3K pathway activity (p-ERK and p-AKT), with concurrent upregulation of NRAS protein in OSUMMER1 and OSUMMER5. Immunostaining revealed inconsistent CD4+ and CD8+ T- cell infiltration across models, suggesting a non-uniform immune response. These findings highlight the complex nature of resistance to pan-RAS inhibition in vivo, implicating both signaling reactivation and tumor-intrinsic heterogeneity in therapeutic escape. This work underscores the need to pair pan-RAS inhibitors with epigenetic or immunologic strategies to enhance treatment durability in NRAS-mutant melanoma.

Source:

Columbia / Comparative Literature / 2028

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Co-authors:

Alisa Gulyansky