the phosphoinositide 3-kinase ( pi3k)/akt survival pathway functions upstream to positively regulate the activity of the mtor axis . recent studies show that extracellular signal - regulated kinases 1/2 ( erk1/2 ) and 90 kda ribosomal protein s6 kinase 2 ( rsk2 ) also positively regulate mtorc1 through respective phosphorylation of tsc2 and raptor , linking ras to positive regulation of mtorc1 signaling , . thus , mtor serves as a convergence point of the pi3k / akt and mitogen - activated protein kinase ( mapk)/erk signaling pathways , which are often hyperactivated in cancer . in contrast , the tumor suppressors liver kinase b1 ( lkb1 ) and p53 both negatively regulate the mtor axis . lkb1 inhibits mtorc1 signaling through activation of amp - activated protein kinase ( ampk ) and tsc2 . similarly , p53 inhibits mtor1 signaling through sestrin - mediated activation of ampk and tsc2 , . hence , alteration ( e.g. , activation and inactivating mutations ) of genes ( e.g. , pten , kras , and lkb1 ) whose products regulate the mtor axis will result in hyperactivation of the axis in certain types of cancers ( figure 1 ) . this category of cancer is expected to be  addicted  to the mtor axis for survival and growth , hence increasing susceptibility to mtor - targeted therapy . compared with mtorc1 signaling , little is known about the upstream regulators of the mtorc2 axis . various oncogenes ( e.g. , ras and pik3ca ; in blue ) or tumor suppressors ( e.g. , pten , lkb1 and p53 ; in red ) positively or negatively regulate the mtorc axis . mtor , mammalian target of rapamycin ; pik3ca , phosphoinositide-3-kinase , catalytic , alpha polypeptide ; pten , phosphatase and tensin homolog ; lkb1 , liver kinase b1 ; mtorc , mammalian target of rapamycin complex . the tumor suppressor pten is a lipid phosphatase that negatively regulates the pi3k signaling pathway . sawyers 's group revealed that pten - deficient mouse cells or human cancer cells showed enhanced sensitivity to cci-779 , both in vitro and in vivo . soon after that study , shi et al . reported similar findings in multiple myeloma cells . they found that 3 of 4 pten - deficient cell lines with constitutively active akt were remarkably sensitive to growth inhibition and g1 arrest induced by cci-779 , with id50 concentrations of < 1 nmol / l . in contrast , myeloma cells expressing wild - type pten were > 1,000-fold more resistant . acute expression of a constitutively active akt gene in cci-779resistant myeloma cells containing wild - type pten and quiescent akt did not convert them to the cci-779sensitive phenotype . conversely , expression of wild - type pten in cci-779-sensitive , pten - deficient myeloma cells did not induce resistance . thus , the level of pten and akt activity does not regulate sensitivity per se . in a recent study , suppressing pten function by expressing a pten mutant lacking lipid ( g129e ) or lipid and protein ( c124s ) phosphatase activity in mcf-7 cells conferred sensitivity to rapamycin . pi3ks are heterodimeric lipid kinases composed of p110 catalytic and p85 regulatory subunit variants encoded by separate genes and alternative splicing . mutations in the p110 catalytic subunit ( pi3kca ) occur in certain types of cancer , such as breast cancer , and lead to the activation of pi3k / akt signaling . in a study with 31 breast cancer cell lines , weigelt et al . reported that breast cancer cells harboring pik3ca mutations , but not pten loss , were selectively sensitive to rad001 and the mtor kinase inhibitor pp242 . however , in another study with 31 human cancer cell lines , meric - bernstam et al . reported that cell lines with pik3ca and/or pten mutations were more likely to be rapamycin - sensitive . interestingly , di nicolantonio et al .   recently reported that human cancer cells carrying alterations in the pi3k pathway were responsive to rad001 , both in vitro and in vivo , except when kras mutations occurred concomitantly or were exogenously introduced . in cancer cells with mutations in both pik3ca and kras , genetic ablation of mutant kras reinstated response to the drug . mahoney et al . reported that lkb1/kras mutant nsclcs constitute a genetic subset of nsclc with increased sensitivity to mapk ( ci-1040 ) and mtor ( rapamycin ) signaling inhibition , whereas lkb1 and kras mutations alone do not confer similar sensitivity . contreras et al . reported that lkb1 inactivation - driven endometrial cancer is highly responsive to rapamycin monotherapy . in their study , they found that rapamycin monotherapy not only greatly slowed disease progression , but also led to striking regression of pre - existing tumors . to date , few clinical studies have investigated the impact of genetic alterations on mtor - targeted cancer therapy . in a cohort of metastatic cancer patients who had received single - agent rad001 , di nicolantoni et al .   found that the presence of kras mutations was significantly associated with lack of benefit ( partial response and stable disease ) after rad001 therapy . in this study , 11 of the 12 patients with kras mutant tumors had disease progression , whereas 15 of 31 of wild - type cases benefited from treatment ( p = 0.0171 ) . unfortunately , the impact of pik3ca mutations on patient response to treatment was not analyzed because of limited sample size . recently investigated the genetic basis of remission of a patient with metastatic bladder cancer treated with rad001 using whole - genome sequencing . they found that the mutation of tsc , which occurs in about 8% of bladder cancer cases , correlated with rad001 sensitivity . after identification of tsc1 mutation from this responsive bladder cancer case , the authors further analyzed samples from 13 additional bladder cancer patients treated with rad001 in the same trial . this analysis revealed 3 patients with tumors harboring nonsense mutations in tsc1 , including 2 patients who had minor responses to rad001 ( 17% and 24% tumor regression ) . a fourth patient with 7% tumor regression had a somatic missense tsc1 variant of unknown functional consequence . in contrast , tumors from 8 of the 9 patients showing disease progression were tsc7-wild type . benefit from rad001 lasted longer in patients with tsc1-mutant tumors than in those with wild - type tumors ( 7.7 months vs. 2.0 months , p = 0.004 ) , with a significant improvement in time to recurrence ( 4.1 months vs. 1.8 months ; p = 0.001 ) . sega is a benign , slow - growing tumor that usually forms in the walls of fluid - filled spaces in the brain . it is common in patients with tsc , which is caused by the mutation of tsc1 or tsc2 gene . in an early single - arm trial , rad001 reduced sega tumor volume 50% in 9 of 28 patients aged 3 to 34 years . in the recently completed double - blind , placebo - controlled phase iii trial involving 117 patients with tsc in 24 centers across 10 countries worldwide , 24 weeks of oral rad001 treatment caused 50% reduction in sega tumor volume in 35% ( 27/78 ) of patients , whereas placebo did not have this effect in any patient ( 0/39 ) . these results prompted fda approval of rad001 for the treatment of pediatric and adult sega . in a prospective clinical trial , janku et al . sequenced pik3ca in tumor samples from patients with advanced breast , cervical , endometrial , and ovarian cancers that were refractory to standard therapies . of the 140 patients analyzed , 25 ( 18% ) had phoca mutations , and 23 were then enrolled in a clinical trial that included a pi3k / akt / mtor pathway inhibitor ( e.g. , cci-779 alone ; cci-779 plus bevacizumab ; rapamycin plus docetaxel ; or cci-779 , bevacizumab plus liposomal doxorubicin ) . partial response was observed in 30% ( 7/23 ) of the patients harboring a pik3ca mutation . in contrast , only 10% ( 7/70 ) of patients with wild - type pik3ca who were treated on the same protocols and had the same disease types responded to treatment ( p = 0.04 ) . thus , this study suggests that screening for pik3ca mutations may reveal a subset of patients who are sensitive to treatment regimens that include a pi3k / akt / mtor inhibitor . several preclinical studies have consistently suggested that tumors with pik3ca mutations are likely to be sensitive to rapalog monotherapy . however , the clinical data to confirm these preclinical findings are largely lacking , although a clinical study has shown that patients with pik3ca mutations responded better than those without the mutation to treatment regimens with a pi3k / akt / mtor inhibitor . moreover , preclinical data regarding the impact of pten mutation or loss on cancer cell response to mtor inhibition are not consistent and need further clarification or validation , particularly in the clinic . the finding of an association between kras mutations and cell resistance to rapalogs   is intriguing . another important observation is that the concomitant presence of kras and pik3ca mutations may confer resistance to rad001 , though mutations in pik3ca alone predict cell sensitivity to rad001 . it is crucial to fully understand the biological bases or molecular mechanisms for these findings . in this way , we may eventually develop more efficacious , mechanism - driven therapeutic strategies to overcome resistance . although mutations in pik3ca and/or pten seem to impact cancer cell sensitivity to mtor - targeted therapy , this may not be helpful for predicting the sensitivity of cancers in which these genes have low mutation rates , such as nsclc ( < 10% for combination of pik3ca and pten ) , . this also applies to the findings that lkb1 mutation or inactivation confers cell sensitivity to rapalogs , , since lkb1 is primarily mutated in nsclc ( up to 30% ) but is rarely mutated in other cancers . nonetheless , we have made considerable progress towards identifying subsets of cancer patients who may benefit from mtor - targeted therapy , though some studies are preliminary so far . these efforts represent the first step toward personalized mtor - directed cancer medicine . considering the limited single - agent activity of rapalogs in the majority of cancers , development of rapalog - based combination regimens one successful example is the combination of rad001 and exemestane for the treatment of advanced hormone receptor  positive , her2-negative breast cancer in postmenopausal women . however , the impact of genetic alterations on tumor response to rapalog - based combination treatments is largely unknown . demonstration of effective and mechanism - driven rapalog - based combination regimens in patients should be a key effort in this direction .
rapamycin and its derivatives ( rapalogs ) , a group of allosteric inhibitors of mammalian target of rapamycin ( mtor ) , have been actively tested in a variety of cancer clinical trials , and some have been approved by the food and drug administration for the treatment of certain types of cancers . 
 however , the single agent activity of these compounds in many tumor types remains modest . 
 the mtor axis is regulated by multiple upstream signaling pathways . because the genes ( e.g. , pik3ca , kras , pten , and lkb1 ) that encode key components in these signaling pathways are frequently mutated in human cancers , a subset of cancer types 
 may be addicted to a given mutation , leading to hyperactivation of the mtor axis . 
 thus , efforts have been made to demonstrate the potential impact of genetic alterations on rapalog - based or mtor - targeted cancer therapy . 
 this review will primarily summarize research advances in this direction .