Table 2.

Examples of clinically targeted oncoproteins and the associated post-translational modifications responsible for cancer therapeutics.

Oncoprotein	Description
Signal transducer and activator of transcription 3 (STAT3)	Studies have shown that knockdown of Raf Kinase Inhibitor Protein (RKIP, negative regulator of Ras-MAPK/ERK signaling pathway) in NSCLC patients, causes STAT3 phosphorylation and activation Sleading to metastasis in A549 and NCI-H1299 cell lines (1, 2).
Epidermal Growth Factor Receptor (EGFR)	In NSCLC patients, palmitoylation of EGFR oncoprotein at Cys797 site by ZDHHC1, ZDHHC2, and/or ZDHHC21 enzymes (Zinc finger DHHC-type containing enzymes) leads to receptor dimerization, stability, and its subsequent activation (3). When EGFR palmitoylation is inhibited using broad spectrum protein palmitoylation inhibitors such as 2-bromopalmitate (2-BP), the lethal efficacy of its targeted inhibitor, Gefitinib increases (3).
N-acetylgalactosaminyltransferases (GALNTs)	GALNTs are group of enzymes that are responsible at modulating initial mucin-type O-glycosylation, which have shown close relationship with cancer incidence and metastasis (4, 5). Previous animal studies have extensively reported that GALNT class of enzymes (GALNT1-GALNT20) act as prognostic markers for different cancers, or have been linked to alterations in cellular characteristics including cell proliferation, migration, invasion and metastasis in experimental models (6). Few of the broad range of cancers in which altered protein levels of GALNTs have been demonstrated include colorectal (7), gastric (8), breast (9), pancreatic (10), lung adenocarcinoma (11), NSCLC (12), and glioma (13). Studies showed that GALNT2 promotes tumor formation and progression in BALB/c nude mice models (14). Many transmembrane proteins are modified by N-linked glycosylation, which is responsible for tumor metastasis. This study also demonstrates that N-glycosylation of T-cell membrane protein-4 (TIM-4) at Asn291 site is conducive to cancer metastasis as reported in vitro and in vivo models (15).
RAS	The RAS family of GTPases are small monomeric G-proteins that regulate key biological functions like gene expression, transmembrane signaling, apoptosis, etc (16). RAS has been extensively studied and play significant roles in cancer initiation and progression. About 25-30% of human tumors harbor RAS mutations. KRAS, NRAS, HRAS are three members of this oncogene superfamily that have been reported to implicate in various malignancies; KRAS in NSCLC, pancreatic cancer; NRAS in liver cancer and in liquid tumors like AML; HRAS mutations in BCa and renal cell cancer (17–19). HRAS oncogene is only farnesylated, but KRAS4A, KRAS4B and NRAS are geranylgeranylated by GGTaseI, leading to activation of downstream signaling of MAPK/ERK pathway (20). Because many tumors rely on RAS oncogenes for their survival, a number of drugs have been developed that selectively target these oncoproteins. Earlier, researchers focused on blocking a type of prenylation PTM known as farnesylation on RAS which exhibited huge promise in preclinical investigations (19). Unfortunately, no therapeutic effects from farnesyl transferase inhibitors could be demonstrated, making RAS challenging to drug, but inhibitors targeting specific RAS mutations are under development (21).
MYC (c-MYC/N-MYC/L-MYC)	MYC family of transcription factors has several roles to play in cellular processes such as cell growth, proliferation, differentiation, and programmed cell death (22). It is deregulated in ~ 70% of human tumors, of which majority are aggressive such as in leukemias and high-grade lymphomas or in cancers which have poorer clinical outcomes like NSCLC (23). Studies have showed that the compound oridonin (a natural terpenoid) upregulates SCFFBXW7 causing degradation of MYC protein via Ub-proteasome system, and therefore leading to apoptosis in leukemia and lymphoma cell lines (24). Aurora kinase A (AURKA) blocks SCFFBXW7-mediated MYC proteolysis by binding MBI motif based on a covalent association that exclusively depends on the phosphorylation status of T58 and S62 sites (25, 26). Overall, strategies are being made to develop small molecules that can inhibit AURKA to indirectly target MYC activity. Drugs such as MLN8237/alisertib and CD532 causes Aurora A-c-MYC/N-MYC complex non-functional and advances the tumor towards regression, as observed in neuroblastoma and human hepatocarcinoma cells (26, 27).