Table 1.

| A summary of agents may be used to target LKB1 mutants and their stages of development.

Class	Agents	Targets / Mechanisms that are LKB1 independent	Stage of development	Comments	Refs
AMPK activators/stress inducers	Metformin	Inhibits mitochondria complex 1 and induces higher AMP/ATP ratio in LKB1 mutants25, 26, 27	Multiple phase 1 to 3 trials in malignancy and diabetes. Some of them included AMPK in the outcome measures (e.g. the phase 2 trial NCT01266486)	The phase 2 NA_00052073 also included LKB1 status in the secondary outcome measures	25, 26, 27
	Phenformin	Targets mitochondria complex 1 and induces more severe energy stress in LKB1 mutants27	Was withdrawn from market in 1978 due to rare but severe lactic acidosis in diabetic pts. Not currently in clinical trial	LKB1 farnesylation is required for activation of AMPK by phenformin30	27, 30
	AICAR	Induces apoptosis in LKB1-null MEF cells and ovarian cancer cells34, 35	Phase 1-2, but none for malignancies at this moment		34, 35
mTOR/HIF-1α/LOX inhibitors	Rapalogues (Everolimus, sirolimus, temsirolimus)	mTORC1	Now in multiple phase 1-3 clinical trials	NCT01178151 is a phase 2 trial specifically for PJS	32, 42, 43
	AZD8055	ATP competitive inhibitor for both mTORC1 and mTORC2	Phase 1 but not specifically for LKB1 mutants	Preferentially reduced both LDH and PDH levels in a STK11−/−/NIC breast cancer model	81
	BAPN	LOX	Laboratory		82
FAK/Src inhibitor	PF573228	FAK inhibition in LKB1-null background53	Laboratory		52, 53
FAK/Src inhibitor CHK1 inhibitors	Defactinib (PF-4554878, VS-6063)	FAK inhibition	Phase 1 & 2 including a trial for KRAS mutant NSCLC, but not specific for LKB1	Needs more studies for LKB1 mutants	72, 73
	Dasatinib	Src inhibition	Phase 1 & 2 for various malignancies. Not LKB1 specific		72, 73
	AZD7762	CHK1 inhibition	Phase 1 (solid tumor). Not LKB1 specific.	Cardiac toxicity83, neutropenia84	72, 73
CHK1 inhibitors Nucleotide metabolism inhibitors	CHIR124	CHK1 inhibition	Laboratory		72, 73
	DTYMK shRNA	DTYMK inhibition, reduce dTTP biosynthesis	Laboratory		72, 73
COPI/lysosomal maturation inhibitors	Bafilomycin A1 (bafA)	Inhibits vacuolar ATPase	Laboratory		72, 73
COPI/lysosomal maturation inhibitors YAP inhibitors/Hippo activators	Saliphenylhalamide A (saliPhe)	Inhibits vacuolar ATPase	Laboratory		72, 73
	Dox-inducible YAP shRNA (iYAP shRNA)	Silences YAP	Laboratory		72, 73
	Verteporfin	Disrupts the TEAD-YAP interaction	Laboratory	Suppresses YAP, but needs to be tested in the setting of LKB1 mutation	27, 30
	Super-TDU	Compete with YAP for the interaction with TEAD	Laboratory	Suppressed YAP and gastric cancer growth. Needs to be tested in LKB1 mutants	27, 30

Only LKB1 independent targets and mechanisms are listed. The information of clinical trials was obtained from www.clinicaltrials.gov. Although some of the listed agents have already been enrolled in clinical trials, only very few of them were specifically designed for LKB1 mutants. Also, some of the listed agents are still in silencing RNA formula, but due to their potentiality and good mechanistic studies, they are included here as well.

Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside; DTYMK: deoxythymidylate kinase; LOX: lysyl oxidase; BAPN: β-aminopropionitrile; PJS: Peutz–Jeghers Syndrome; LDH: lactate dehydrogenase; PDH: pyruvate dehydrogenase; NIC: Neu/HER2-MMTV-Cre.