2022 Undergraduate Research Symposium

Winners ðŸ†: Neel Patel (biomedical physics) and Mariana Sierra (neuroscience)

Faculty mentor: Mindy Huang

Abstract

The Kristen Rat Sarcoma (KRAS) protein, encoded by the KRAS gene, is a signal transducer that plays a crucial role in regulating cell proliferation. KRAS mutations have been known to cause lung, colorectal, and pancreatic cancers. Previously, KRAS was considered an "undruggable" target. However, with better understanding of the protein's biology paired with advanced new technologies, the FDA approved the first KRAS inhibitor (sotorasib) for lung cancer patients with the KRASG12C mutation in 2021, expressing the recent interest of targeted drugs for KRAS.

In clinical trials, sotorasib proved ineffective for pancreatic and colorectal cancers with the G12C mutation. Irrespective of mutant identity, oncogenic KRAS requires activation by the guanine nucleotide exchange factor (GEF) Son of Sevenless 1 (SOS1), highlighting an exploitable vulnerability with broad therapeutic applicability. The goal of this study is to develop novel pan-KRAS inhibitors by targeting the KRAS-SOS1 interactions through computational modeling. To start, we applied Gaussian accelerated molecular dynamics (GaMD) simulation, an advanced conformational sampling method, to collect the nature of the KRAS protein motion in solution. Then, the clustering analysis method was used to assemble KRAS conformational structures into ten groups for later virtual screening and docking simulations.

We aim to address 20 to 30 compounds to later be experimentally assessed for their (1) ability to disrupt the KRAS-SOS1 interactions and (2) cytotoxicity in KRAS mutation-bearing cell lines. The work will provide insights in the drug efficacy of KRAS inhibitors and give rise to a novel set of KRAS candidates to be used in clinical oncogenic treatments.

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