Table 4.

Clinical trials with combinations between targeted therapies in which the first inhibit resistance mechanisms of the second.

Signalling Pathways	Targeted Therapy	Clinical Trial Phase	Type of Tumor	Rationale	References
ALK AND CDK4/6	Ceritinib + Ribociclib	Phase I completed	NSCLC	ALK+ NSCLC tumors	[149]
		Ongoing phase I	Neuroblastoma	In vitro synergy (lower phospho-RB1 levels only in ALK+ NB cells)	[150,151]
MET AND AR	Crizotinib + Enzalutamide	Ongoing phase I	mCRPC	AR inhibition upregulates MET (off-target effect for crizotinib)	[152,153]
PDGFR AND C-SRC	Crizotinib + Dasatinib	Ongoing phase I	Solid malignancies	Downstream effects of MET require c-Src, whose inhibition upregulates MET	[154,155]
		Phase I completed	High-grade glioma	PDGFR upregulated in gliomas (off-target for dasatinib)	[156]
PI3K AND EGFR	Copanlisib + Cetuximab	Ongoing phase Ib/II	HNSCC	Aberrant PI3K signaling confers resistance to cetuximab and both pathways are upregulated in HNSCC	[157,158]
VEGFR AND MTOR	Pazopanib + Everolimus	Ongoing phase I	Solid tumors	mTOR pathway activation confers resistance to anti-VEGF therapy	[159]
BCR	Idelalisib + Entospletinib	Phase II completed	Lymphoid malignancies	Synergistic effect with simultaneous inhibition of multiple kinases in the BCR pathway (PI3K and Syk), but limited by severe life-threatening adverse effects.	[160]
CDK4/6 AND PI3K/MTOR	Abemaciclib + LY3023414	Ongoing phase II	PDAC	Enhanced PI3K/mTOR activity confers resistance to CDKi therapy	[161]
	Ribociclib + Everolimus	Ongoing phase II	mPDAC		[105]
CDK4/6 AND EGFR	Palbociclib + Cetuximab	Ongoing phase II	HNSCC	EGFR overexpression is an oncogenic driver and there is either a frequent loss of CDKN2A or amplification of CCND1	[162]
CDK4/6 AND MEK	Palbociclib + Trametinib	Phase Ib completed	Advanced solid malignancies	CDK activity confers resistance to MEKi	[163,164]
BRAF AND MEK	Dabrafenib + Trametinib	Ongoing phase II	Melanoma and brain metastases	MAPK pathway reactivation confers resistance to BRAFi. Melanoma brain metastasis seem to lack ABCB1 expression. Combination can cross blood-brain barrier.	[165]
	Vemurafenib + Cobimetinib	Ongoing phase II			[166]
VEGFR AND EGFR	Bevacizumab + Erlotinib	Phase II completed	Advanced or Metastatic Liver Cancer	Dual blockade of tumor neovascularization and proliferative signaling.	[167]

Abbreviations: HNSCC - Head and neck squamous cell carcinoma, mCRPC - metastatic castration-resistant prostate cancer, mPDAC - metastatic pancreatic duct adenocarcinoma, NSCLC - non-small cell lung cancer, PDAC - Pancreatic duct adenocarcinoma.