Neomorphic mutations create therapeutic challenges in cancer

Abstract

Oncogenesis is a pathologic process driven by genomic aberrations, including changes in nucleotide sequences. The majority of these mutational events fall into two broad categories: inactivation of tumor suppressor genes (hypomorph, antimorph or amorph) or activation of oncogenes (hypermorph). The recent surge in genome sequence data and functional genomics research has ushered in the discovery of aberrations in a third category: gain-of-novel-function mutation (neomorph). These neomorphic mutations, which can be found in both tumor suppressor genes and oncogenes, produce proteins with entirely different functions from their respective wild-type (WT) proteins and the other morphs. The unanticipated phenotypic outcomes elicited by neomorphic mutations imply that tumors with the neomorphic mutations may not respond to therapies designed to target the WT protein. Therefore, understanding the functional activities of each genomic aberration to be targeted is crucial in devising effective treatment strategies that will benefit specific cancer patients.

Figure 1.. IDH1 R132H and IDH2 R172K/R140Q reduce α-KG to the oncometabolite 2-HG.

WT IDH2 and IDH2 reduce NADP+ and convert isocitrate into α-KG, which is a co-substrate of α-KG-dependent enzymes including PHD, TET2, and JHDM to regulate HIF-1α stability and epigenetic modifications. IDH1 R132H and IDH2 R172K/R140Q do not catalyze the conversion of isocitrate into α-KG but instead reduce α-KG to 2-HG. Competition of 2-HG with α-KG for binding to the α-KG-dependent enzymes results in DNA/histone methylation, HIF-1α stabilization and subsequent gene transcription (e.g. VEGF) to promote stem cell maintenance and angiogenesis.

Figure 2.. p110α helical domain neomorphs bind to IRS1 for stabilization and activation independent of its canonical partner p85.

Upon RTK activation, p485 binds to phosphorylated IRS1 that thereby activates p110α. p110α neomorphs in the helical domain directly associate with IRS1 independent of p85 and growth factor stimulation. This association stabilizes and activates p110α, thereby promoting PI(3,4,5)P₃ production and in vivo tumor growth through AKT signaling. Another independent study showed that these mutants increase membrane localization and activation of PDK1, which in turn promotes anchorage-independent growth through SGK3 activation. The detailed mechanism underlying the activation of PDK1 and whether PDK1 activation is a consequence of neomorphic activity remain to be revealed. RTK, receptor tyrosine kinase.

Figure 3.. PIK3R1 neomorphs activate PI3K and MAPK signaling.

p6α neomorphs activate ERK and JNK signaling pathways to promote cell growth, survival, invasion and inhibit apoptosis. Binding of neomorphs to Cdc42 and Rac1 leads to phosphorylation of Braf, MKK1/2 and ERK1/2 in the cytoplasm. Cdc42 and Rac1 also facilitate the translocation of p85α neomorphs from the cytoplasm to the nucleus, where the neomorphs act as scaffolds for a MLK3/MKK7/JNK1/JNK2 complex that activates nuclear JNK signaling. The neomorphs also activate AKT but the mechanism is unknown. RTK, receptor tyrosine kinase. GPCR, G protein-coupled receptor.

Figure 4.. PTEN A126G has altered enzymatic activity.

WT PTEN inhibits the activation of PI53K/AKT signaling by dephosphorylating PI(3,4,5)P₃ and PI(3,4)P₂ to PI(4,5)P₂ and PI(4)P respectively. PTEN A126G, when compared to WT PTEN, dephosphorylates PI(3,4,5)P₃ at reduced rate. Moreover, PTEN A126G displays a shift in enzymatic specificity toward 5’ phosphoinositides, resulting in the production of PI(3,4)P₂ rather than PI(4,5)P₂ which is produced by WT PTEN. The accumulation of PI(3,4,5)P₂ and PI(3,4)P₂ together leads to AKT and S6 phosphorylation and ultimately cell motility.

Figure 5.. p53 neomorphic mutants gain novel interacting partners leading to pro-oncogenic activities.

(a) p6 and p73 form homotetramers or heterotetramers that activate transcription of genes promoting cell apoptosis and sensitivity to chemotherapeutic drugs. p63 or p73 do not interact with WT p53. Neomorphic p53 mutants bind to p63 and p73 homotetramers or heterotetramers and inhibit p63-/p73-mediated gene transcription leading to increased chemoresistance, cell migration and invasion. (b) WT p53 binds to the transcription factor NF-Y and recruits the histone deacetylase HDAC1 as a co-factor to inhibit the transcription of NF-Y target genes involved in cell cycle progression such as CCNA, CCNB, CDK1, and CDC25C. Neomorphic p53 mutants recruit histone acetyltransferase p300, an opposing histone modifying enzyme, to promote the transcription of NF-Y target genes. (c) Neomorphic p53 mutants, but not WT p53, bind to Mre11. The interaction impairs the recruitment of Mre11 to double-strand DNA breaks and inhibits the activation of ATM thereby preventing DNA repair.