Multiple Molecular Targets Associated with Genomic Instability in Lung Cancer

Table 1

Recent molecular therapies and biomarkers targeting elements of genomic instability in LC.

	Target	Therapy	Reference	Rationale
Cell cycle	Wee1	AZD1775	[41]	Study of a selective inhibitor of the tyrosine kinase Wee1 that impairs CDK1/2 activity inducing cell cycle arrest at G2 and intra-S checkpoints.
	CDK4/6	Palbociclib	[42]	Blocking cyclin-dependent kinases CDK4 and CDK6 represses the G1/S transition in the cell cycle inhibiting cancer cell proliferation.
	CDK1/2	Dinaciclib	[43]	Dinaciclib inhibits CDK1 and CDK2 inducing anaphase catastrophe, apoptosis, and cell death and represents a potential treatment for LC.
	Pan-CDKs	Roniciclib	[44]	Cancer cells overexpress cyclins and CDKs; therefore, blocking multiple CDKs induces cell cycle arrest and apoptosis and reduces tumorigenesis.
	Cyclin D1/CDK4	Simvastatin	[45]	Simvastatin downregulates protein levels of cyclin D1 and CDK4 while upregulating expression of p16 and p27 that inhibit CDK activity.
DNA repair	PARP	Olaparib	[46]	A poly(ADP-ribose) polymerase (PARP) inhibitor that blocks DNA repair and in combination with other agents can induce synthetic lethality in cancer cells.
	ATR	M6620	[47]	An ataxia telangiectasia and rad3-related (ATR) kinase inhibitor that blocks DNA repair after damage induced by the chemotherapeutic agent topotecan.
	AlkBH3	Indenone derivatives	[48]	AlkB homologue-3 (AlkBH3) participates in direct reversal of DNA damage. Inhibiting this dealkylation enzyme prevents carcinogenesis and metastasis.
	ERCC1-XPF	NSC16168	[49]	ERCC1-XPF participates in the NER mechanism removing DNA adducts caused by cisplatin; targeting this enzyme can sensitize cells to chemotherapy.
	DNA-PKcs	NU7026	[50]	The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is fundamental for DNA double-strand break (DSB) repair and radiosensitivity.
Mitotic control	PLK1	BI2536	[51]	PLK1 binds to Bub1 and contributes to the regulation of proper chromosome segregation by stabilizing the spindle assembly checkpoint (SAC) complex.
	TTK	CFI402257	[52]	Monopolar spindle 1 (MPS1) or TTK regulates SAC activity being fundamental for genome maintenance during mitosis; therefore, it is an attractive target.
	AurA	LY3295668	[53]	Retinoblastoma (RB1) protein regulates G1/S transition, together with the mitotic checkpoint AurA that creates synthetic lethality in refractory LC.
	Mps1	TC Mps1 12	[54]	This inhibitor of a SAC element leads to accumulation of chromosomal alterations by missegregation, i.e., aneuploidy and cytotoxicity in A549 cells.
	CDC20	Biomarker	[55]	CDC20, part of the MCC, is overexpressed and confers poor prognosis in LC exacerbating pleural invasion and reducing 5-year overall survival.