Role of Akt signaling in resistance to DNA-targeted therapy

Table 1 Drugs targeting phosphatidylinositol 3 kinase/Akt/mammalian target of rapamycin pathway

PI3K/Akt/mTOR subgroups	Agents	Clinical Stage
Pan-PI3K inhibitors	XL147	Phase II
	BKM120	Phase III
	GDC0941	Phase II
Rapalogues (mTORC1 inhibitors)	Sirolimus	Phase III
	Everolimus	Approved
	Temsirolimus	Approved
	Ridaforolimus	Phase III
mTORC1/2 inhibitors	INK128	Phase II
	AZD8055	Phase I
	OSI027	Phase I
PI3K–mTOR inhibitors	BEZ235	Phase II
	XL765	Phase II
	GSK1059615	Phase I
Isoform-specific PI3K inhibitors	CAL-101 (p110δ)	Phase III
	INK1117 (p110α)	Phase I
	BYL719 (p110α)	Phase II
Akt inhibitors	Perifosine	Phase III
	MK-2206	Phase II
	GDC0068	Phase II
	GSK690693	Phase I

PI3K: Phosphatidylinositol 3 kinase; mTOR: Mammalian target of rapamycin.

Table 2 Systematic chart of searching methodology and the results based on PubMed

DNA-targeted therapies	Agents	Akt modulation
		All papers1	Non-original2	Relevant papers3	PI3K/Akt inhibitors4
					LY294002	Wortmannin	BEZ235	Perifosine	MK2206
Platinum	Carboplatin	68	6	51	3	1	0	0	4
	Cisplatin	631	15	589	85	22	8	9	5
	Oxaliplatin	71	5	59	5	2	0	0	0
Taxane	Docetaxel	149	13	127	9	2	3	1	3
	Paclitaxel	363	18	331	47	15	4	2	5
Antimetabolite	Fluorouracil	191	5	174	18	6	0	2	3
	Gemcitabine	213	14	191	16	8	3	1	1
	Pemetrexed	35	3	32	5	2	1	0	0
Radiation	Irradiation/radiation	1649	186	1356	151	82	12	13	5
Total articles	(9 agents)	3370	265	2910	339	140	31	28	26

¹Terms used in the search: Query agent/radiation, and Akt, within whole the article with no language limitation, as of September, 2014;

²Including the retracted publication, duplicate publication or non-original papers, including Review articles, Letters and Editorials, Comments, Case Reports, etc.;

³Relevant with regard to the modulation of Akt by the query agent. [p-Akt OR pAkt OR "phospho-Akt" OR (phosphorylat* Akt) OR “Akt phosphorylation” OR “Akt inhibition” OR “Akt modulation” OR (inhibit* Akt) OR “inactivation of Akt” OR “Akt inactivation” OR “activation of Akt” OR “inactivating Akt”];

⁴Suppressing Akt cascade by a PI3K/Akt inhibitor to sensitize the query agent. PI3K: Phosphatidylinositol 3 kinase.

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.

Table 4 Clinical trials on phosphatidylinositol 3 kinase/Akt inhibitors in combination with DNA-targeted agents

PI3K/Akt inhibitor	Target(s)	Combination arm(s)	Condition	Trial phase/status	Trial/registration
MK-2206	Akt	Carboplatin + paclitaxel, docetaxel, erlotinib	Locally advanced, metastatic solid tumors	I/completed (published)	NCT00848718/February 2009[170]
		Paclitaxel, trastuzumab	HER2-overexpressing advanced solid tumors	I/completed (abstract is published)	NCT01235897/November 2010[171]
		Paclitaxel	Adult solid neoplasm,	I/ongoing (unpublished)	NCT01263145/December 2010
			recurrent or metastatic breast cancer
Perifosine	PI3K/Akt	Docetaxel, prednisone	Neoplasms	I/completed (abstract is published)	NCT00399087/November 2006[172]
		Docetaxel	Recurrent ovarian cancer	I/completed (abstract is published)	NCT00431054/February 2007[173]
		Paclitaxel	Neoplasms	I/completed (abstract is published)	NCT00399126/November 2006[174]
		Gemcitabine	Neoplasms	I/completed (abstract is published)	NCT00398697/November 2006[175]
		Radiation	Solid tumors	I/published	Vink et al[176]
		Radiation	Biochemically recurrent, hormone-sensitive prostate cancer with previous prostatectomy and/or radiation therapy	II/published	Chee et al[177]
BEZ235	PI3K/mTOR	BEZ235 + paclitaxel, BKM120 + paclitaxel, BEZ235 + paclitaxel + trastuzumab, BKM120 + paclitaxel + trastuzumab	Metastatic or locally advanced solid tumors	I/completed (abstract is published)	NCT01285466/January 2011[178]
		Paclitaxel	Inoperable locally advanced breast cancer, metastatic breast cancer	I and II/completed (abstract is published)	NCT01495247/September 2011[179]

HER2: Human epidermal growth factor receptor 2; PI3K: Phosphatidylinositol 3 kinase; mTOR: Mammalian target of rapamycin.