Targeting the HER Family in KRAS Mutant Colorectal Cancer - ABSTRACT It is estimated that more than 53,000 people in the U.S. will die of colorectal cancer (CRC) in 2024 with an alarming incidence and mortality rate especially among individuals younger than 50 years old. About 41% of colorectal cancer patients have a KRAS mutation. This small protein acts as molecular switch, transitioning from an active (GTP-bound) to an inactive (GDP-bound) state. In the past two decades with advances in drug discovery, therapeutic modeling, medicinal chemistry, genomic sequencing, and pre-clinical validation, the once undruggable KRAS became druggable with small molecule inhibitors targeting KRASG12C demonstrating efficacy and clinical trials underway with KRAS inhibitors. However, responses occur only in a fraction of patients and among responders, resistance invariably occurs. We have found that there is a striking increase in total HER2 and HER3 levels in CRC cells and patient-derived organoids (PDOs) bearing KRASG12D mutations when treated with the KRASG12D inhibitors MRTX1133 and RMC-9805. This adaptive response could limit the efficacy of KRAS inhibitors. We present preliminary data herein that genetic knockdown of both KRAS and HER3 in CRC cells bearing hotspot mutant KRAS results in a statistical reduction in cell proliferation in comparison to genetic knockdown with only KRAS or HER3. The proposal examines novel treatment strategies of a combination of KRAS inhibitor with a HER3 antibody-drug conjugate containing the payload exatecan. Exatecan is a more potent topoisomerase I inhibitor over SN-38 or DXd and is less susceptible to efflux by the multidrug resistance transporters of the ATP-binding cassette family. Based on our preliminary data and colorectal cancer patient analysis, we hypothesize that colorectal cancers use HER and mutant KRAS to optimize oncogenic signaling, at a baseline and upon treatment with KRAS inhibitors. The objectives are to determine if co-targeting HER3 and KRAS is efficacious in KRAS mutant CRC and delineate adaptive responses to treatment. We will test this hypothesis using the following two aims: 1) To determine the efficacy of co-targeting HER and KRAS in CRC cell lines and patient-derived xenografts (PDXs); 2) To determine the adaptive response in PDXs treated with pharmacological inhibitors of KRAS and HER by exome, transcriptome, and molecular analysis. Our goal is to expand our initial studies in vitro co-targeting mutant KRAS and HER to in vivo studies in PDXs using pharmacological inhibitors of KRAS and HER. Molecular profiling of patients’ tumors is commonplace in the clinic, and more patients with KRAS-mutant and HER3-mutant cancers are being identified than ever before. There are currently no approved therapies for this CRC subtype. Thus, we aim to identify the most effective treatment options for this population. Since several KRAS and HER family inhibitors are already approved for use in patients with cancer, these studies have the potential to be rapidly translated to the clinic. Further, these studies will increase our basic understanding of KRAS and ERBB receptor-driven tumor progression, which can be applied to a larger number of human cancers.
