Role of Akt signaling in resistance to DNA-targeted therapy

Table 3 Studies evaluating the efficacy of phosphatidylinositol 3 kinase phosphatidylinositol 3 kinase/Akt modulators on the apoptotic profile of cisplatin, paclitaxel, gemcitabine and pemetrexed

PI3K/Akt inhibitor and DNA-targeted agent combination	Akt modulation (phosphorylation)
	Lung cancer and mesothelioma		Pancreatic cancer		Ovarian cancer		Malignant glioma
	Synergistic	Antagonistic	Synergistic	Antagonistic	Synergistic	Antagonistic	Synergistic	Antagonistic
LY294002/Cisplatin	1[51]a	1[50]	2[30,31]	-	6[42,56-60]	1[49]	2[62,63]b	1[48]
LY294002/Paclitaxel	2[64,65]	2[50,66]	-	-	7[32,56,67-71]b	-	1[63]	-
LY294002/Gemcitabine	1[72]	1[73]	4[74-77]b	1[78]	1[56]	-	-	-
LY294002/Pemetrexed	1[79]	1[50]	-	-	-	-	-	-
Wortmannin/Cisplatin	1[52]		-	-	3[41-43]	-	-	-
Wortmannin/Paclitaxel	1[80]	-	-	-	1[70]	-	1[80]	-
Wortmannin/Gemcitabine	-	-	5[74,81-84]	-	-	-	-	-
Wortmannin/Pemetrexed	1[79]	-	-	-	-	-	-	-
BEZ235/Cisplatin	1[53]	-	-	-	1[61]	-	-	-
BEZ235/Paclitaxel	-	-	-	-	1[61]	-	-	-
BEZ235/Gemcitabine	-	-	1[85]	-	-	-	-	-
BEZ235/Pemetrexed	1[86]	-	-	-	-	-	-	-
Perifosine/Cisplatin	2[44,54]	-	-	-	2[25,87]	-	-	-
Perifosine/Paclitaxel	-	-	-	-	1[88]	-	-	-
Perifosine/Gemcitabine	1[54]b	-	-	-	1[89]	-	-	-
Perifosine/Pemetrexed	-	-	-	-	-	-	-	-
MK2206/Cisplatin	2[51,55]	-	-	-	-	-	-	-
MK2206/Paclitaxel	-	-	-	-	-	-	-	-
MK2206/Gemcitabine	2[54,90]b	-	-	-	-	-	-	-
MK2206/Pemetrexed	-	1[54]c	-	-	-	-	-	-
Total	17	6	12	1	24	1	4	1

^aChowdhry et al[51]. Reporting an increased sensitivity, but synergism not evaluated;

^bShingu et al[62,63], Kawaguchi et al[69], Pinton et al[54] additive enhancement of proliferative inhibition;

^cHolcomb et al[76] LY294002 combination with gemcitabine showed additive effects on proliferative inhibition in PANC-1 and synergistic in PaCa²⁺ pancreatic cancer cell lines. However, pAkt levels rebounded at later time points. PI3K: Phosphatidylinositol 3 kinase.