Table 1.

miRNAs involved in resistance to targeted therapies in GI cancers.

Targeted Therapies Class	Type of Cancer	MiRNAs Involved	Gene Mechanism Involved	Action
Anti-EGFR	mCRC	Let-7	KRAS downregulation activity	1.high levels were significantly associated with better survival outcome in patients with KRAS mutation [31,32]
		miR-31-5p/miR-31-3p	BRAF activation and role in the signaling pathway downstream of EGFR	2.high levels are associated with TTP and shorter PFS in wt RAS patients treated with cetuximab [33,34,35]
		miR-10/miR-125b	Increasing of Wnt signaling	3.high levels are associated with cetuximab resistance [36]
		miR181a	Inibition of WIF-1	4.high levels are correlated with a longer PFS [37]
		miR-345	EGFR pathway dysregulation	5.high levels are associated with lack of response to cetuximab and irinotecan [38]
		miR-199/miR-375	PHLPP1 and downregulation of Akt pathway	6.high levels correlate with cetuximab resistance [39]
		miR-302	Downregulation of NFIB/ITGA6 axis	7.upregulation restored cetuximab responsiveness [40]
		miR 141-3p	EGFR downstream pathway	8.upregulation improves cetuximab activity [41]
Anti-VEGF	mCRC	miR-126	Enhancing the angiogenic effect of VEGF	9.high levels are associated with resistance to bevacizumab [50]
		miR-664-3p/miR-455-5p	Downregulation of the neuroligin and VRGF system	10.potential predictive tissue biomarkers of bevacizumab effectiveness [51]
		miR-20b-5p/miR-29b-3p/miR-155-5p	Inhibition of Akt pathway/Controlling of HIF-1α signalling	11.high levels are associated with a better outcome of mCRC patients treated with a bevacizumab and chemotherapy [52,53,54]
Anti-HER2	GC	miR-21	PTEN deregulation	12.high levels result in decreased sensitivity to trastuzumab [64]
		miR-223, miR-125b	FBXW7 decrease/PPP1CA downregulation	13.high levels reduce the sensitivity to trastuzumab [67,71]
		miR-16	Akt downregulation via FUBP1 action	14.overexpression is predictors of trastuzumab sensitivity [66]
		miR-200c	EMT block by ZEB1 and ZEB2 targeting	15.downregulated in trastuzumab-resistant GC [70,71]
	GIST	miR-494	FGFR2 reduced expression	16.restores lapatinib sensitivity [75]
RTKs inhibitors	GIST	miR-125a-5p	PTPN18 regulation	17.modulates imatinib response [80]
		miR-320a, miR-518a-5p	Enhanced MCL1 expression via B-catenin/PIK3C2A upregulation	18.downregulated in imatinib-resistant GIST [80,83]
		miR-218	Inhibition of PI3K/AKT pathway	19.overexpression is able to restore the sensitivity to imatinib [82]
		miR-28-5p	NA	20.overexpressed in imatinib resistant GIST samples [87]
	HCC	miR-122, miR-34, let-7, miR-338-3p, miR-93, miR-193a/b, miR-486, miR-101	Downregulation of ADAM10/SRF/Bcl2/Bcl-xL/HIF-1α/CIT-RON/CLDN1/DUSP1	21.overexpression sensitizes HCC cells to sorafenib [89,90,91,92,94,96,97,98,100,102]
	HCC	miR-216a/217, miR-21, miR-221, miR-494	TGF-β and PI3K/AKT pathways activation/inhibition of Caspase 3/mTOR activation	22.overexpression causes chemoresistance against sorafenib [93,95,99,101]
	mCRC	miR-34a	WNT/β-catenin pathway downregulation	23.overexpression sensitizes CRC cells to regorafenib [107]
		miR-30a-5p	Dysregulation of STAT3-HSPA5 axis	24.downregulation is observed in regorafenib-resistant CRC [108]
Immune checkpoint inhibitors	GC	miR-200b, miR-152, miR-570		25.downregulation promotes PD-L1 expression [118]
	mCRC	miR-138-5p, miR-148a-3p		26.overexpression acts by downregulating PD-L1 [122,124]
		miR-200		27.downregulation promotes PD-L1 expression [113]

Abbreviation: mCRC, metastatic colorectal cancer; GC, gastric cancer; GIST, gastrointestinal stroma tumor; TTP, time to progress PFS, progression-free survival; HCC, hepatocellular carcinoma.