Biology subjects

Stites, E.

Publications and source records attributed to Stites, E..

3 recordsLinked to original sources

bioRxiv2024

Increased dosage of wild-type KRAS protein drives KRAS-mutant lung tumorigenesis and drug resistance

Almost 30% of lung adenocarcinomas are driven by activating KRAS mutations. The heterogeneous clinical behavior observed in these cancers could be due to the imbalance of wild-type and oncogenic KRAS alleles. However, the role of RAS dysregulation at the protein level needs to be further explored. A genome-wide global protein stability screen identified the CUL3 ubiquitin ligase adaptor LZTR1, as a major proteostatic regulator of wild-type but not mutant KRAS. In KRAS-mutant lung adenocarcinoma, shallow deletion of LZTR1 is observed in up to 50% of patients and is associated with hypoxic signatures and poorer progression-free disease survival. In a Kras-mutant lung cancer mouse model, heterozygous loss of Lztr1 promoted tumor growth, led to peritumoral vascular remodeling, and limited the response to the KRAS-G12D inhibitor MRTX1133. The vascular alteration in LZTR1-depleted lung cancer was mediated by increased wild-type KRAS protein dosage, which promoted mTOR pathway activation and a subsequent increase in VEGFA secretion. The inhibition of the PI3K/mTOR pathway using dactolisib normalized tumor vasculature, improved drug delivery, and overcame resistance to KRAS-G12D inhibitors. In summary, the dysregulation of RAS proteostasis contributes to lung tumorigenesis, and targeting wild-type KRAS signaling is crucial to overcome intrinsic resistance to inhibitors of mutant KRAS. SignificanceOur study highlights the impact of RAS proteostasis on lung cancer development and progression. Vascular normalization achieved by suppressing wild-type KRAS signaling improved the delivery and response to MRTX1133 in KRAS-mutant lung cancer with shallow LZTR1 deletion.

cancer biology↗

bioRxiv2017

Analysis of RAS as a tumor suppressor

The RAS GTPases are among the best-understood oncogenes that promote human cancer. Many have argued that non-mutated, wild-type, RAS also functions as a tumor suppressor. The arguments for RAS tumor suppressor activity often involve data that are claimed to be inconsistent with known principles of RAS biology. RAS tumor suppressor activity is invoked to explain these observations. Here, we consider an alternative hypothesis: these data are actually consistent with RAS biology. We investigate by using our previously developed mathematical model of RAS regulation. We find that three of five arguments for RAS having tumor suppressor activity are based upon data that the model demonstrates are actually consistent with known RAS biology. We also find that the other two types of data interpreted to indicate a tumor suppressor effect can be explained by our model with the additional assumption that RAS protein expression does not vary proportionally with gene dosage. Measurements of RAS protein expression as a function of gene dosage could help resolve whether or not RAS has tumor suppressor activity. Overall, we conclude that the evidence for RAS having tumor suppressor activity is much less strong that it has appeared.

cancer biology↗

bioRxiv2017

A computational panel of pathological RAS mutants with implications for personalized medicine and genetic medicine

The RAS proteins (KRAS, NRAS, and HRAS) play important roles in multiple diseases. This includes many types of cancer and the developmental syndromes collectively referred to as the RASopathies. There are many different RAS mutants that are found to drive these diseases. Mutant-to-mutant differences pose a challenge for personalized medicine. To investigate this problem, we extend our previously developed model of oncogenic RAS mutants to a total of 16 oncogenic mutants. We also extend our model to RASopathy associated mutants using data for 14 such RAS mutants. The model finds that the known biochemical defects of these mutants are typically sufficient to explain their elevated levels of RAS signaling. In general, our analysis finds that the oncogenic mutants are stronger than the RASopathy mutants. However, the model suggests that RAS signal intensities are spanned by the pathological variants; there does not appear to be a perfect separation between cancer promoting and developmental syndrome promoting mutants. Analysis of the panel also finds that the relative strengths of pathological RAS mutants is not absolute, but rather can vary depending on context. We discuss implications of this finding for personalized cancer medicine and for medical genetics. As genomics permeates clinical medicine, computational models that can resolve mutant specific differences, like the one presented here, may be useful for augmenting clinical thinking with their ability to logically translate biochemical knowledge into system level outputs of perceived clinical relevance.

pathology↗