PI3K/AKT/mTOR信号通路介导索拉非尼治疗原发性肝癌耐药机制的研究进展

索拉非尼（sorafenib）作为原发性肝癌（hepatocellular carcinoma,HCC）靶向治疗的一线药物已广泛应用于临床,然而部分HCC患者对索拉非尼治疗耐药导致临床疗效欠佳,联合其他靶向药物的临床实验仍未取得突破,故深入研究索拉非尼耐药机制,逆转索拉非尼耐药对于改善肝癌治疗的预后具有重要意义。最新研究发现,PI3K/AKT/mTOR信号通路在索拉非尼耐药机制中起重要作用,本文将从PI3K/AKT/mTOR信号通路促进肿瘤血管生成、参与细胞自噬、抑制肿瘤细胞凋亡并促进其增殖、与RAS/RAF/ERK/MEK信号通路交联及其促进上皮-间质转化等几个方面,概述其在索拉非尼治疗原发性肝癌时产生耐药的机制,为进一步开发治疗原发性肝癌的新型药物提供研究方向。     

PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types

The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Molecular alterations in these pathways are implicated in tumorigenesis and resistance to anticancer therapies. The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are known to interact with each other at several nodes, and mounting evidence suggests that dual blockade of both pathways may be required to achieve anticancer effects in certain contexts. This may include tumor types with a high frequency of RAS/RAF/MEK/ERK pathway activation, or situations in which dual pathway strategies may be required to overcome resistance to current targeted therapies. Several clinical studies are currently evaluating the combination of PI3K and MEK inhibitors in a variety of different cancers with certain types of molecular alterations. This review will summarize existing knowledge of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, the cross-talk between them, and the current generation of PI3K and MEK inhibitors that target them. The preclinical rationale for dual pathway inhibition will be discussed within the context of the major tumor types currently being explored in ongoing clinical trials, namely malignant melanoma with BRAF or NRAS mutations, and colorectal, ovarian, pancreatic, and basal-like breast cancers. The emerging clinical profile of PI3K and MEK inhibitor combinations, as reported in Phase I trials, will also be discussed.     

Activated MEK cooperates with Ink4a/Arf loss or Akt activation to induce gliomas in vivo

The RAS/RAF mitogen-activated protein kinase pathway (MAPK) is highly active in many tumor types including the majority of high-grade gliomas and expression of activated RAS or RAF in neural progenitor cells combined with either AKT activation or Ink4a/Arf loss leads to the development of high-grade gliomas in vivo. This strongly suggests that this pathway is necessary for glioma formation and maintenance. To further define the role of this pathway in the development of high-grade gliomas, we used the established RCAS/TVA glioma mouse model to test the ability of activated MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK), a RAF effector, to induce tumors in vivo in the context of activated AKT or Ink4a/Arf loss. Although expression of activated MEK alone in neural progenitor cells is not sufficient for tumorigenesis, the combination of activated MEK and AKT or MEK with Ink4a/Arf loss is transforming. The data reveal that activation of the classical RAS/MAPK pathway, which is mediated through MEK, leads to the development of high-grade gliomas in vivo and suggest that MEK may be a relevant target for glioma therapy. To test this, we treated both mouse and human glioma cells with the MEK inhibitor PD0325901. Although this treatment induced apoptosis in a significant percentage of the cells, the effect was enhanced by combined treatment with the phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235. Our results demonstrate that combined inhibition of MEK and PI3K/mTOR is a rational strategy for the treatment of high-grade gliomas and may be an effective adjuvant therapy for this disease.     

Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma

Acquired resistance to BRAF inhibitors often involves MAPK re‐activation, yet the MEK inhibitor trametinib showed minimal clinical activity in melanoma patients that had progressed on BRAF‐inhibitor therapy. Selective ERK inhibitors have been proposed as alternative salvage therapies. We show that ERK inhibition is more potent than MEK inhibition at suppressing MAPK activity and inhibiting the proliferation of multiple BRAF inhibitor resistant melanoma cell models. Nevertheless, melanoma cells often failed to undergo apoptosis in response to ERK inhibition, because the relief of ERK‐dependent negative feedback activated RAS and PI3K signalling. Consequently, the combination of ERK and PI3K/mTOR inhibition was effective at promoting cell death in all resistant melanoma cell models, and was substantially more potent than the MEK/PI3K/mTOR inhibitor combination. Our data indicate that a broader targeting strategy concurrently inhibiting ERK, rather than MEK, and PI3K/mTOR may circumvent BRAF inhibitor resistance, and should be considered during the clinical development of ERK inhibitors.     

Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade

Mutations of RAS, RAF, and PTEN, all important members of the RAS/MAPK and PI3K/AKT cascades, are reported in a variety of human tumors, including melanomas and endometrial cancer. In endometrial cancer, mutually exclusive mutations of PTEN and KRAS have been reported. On the other hand, mutation of BRAF is highly frequent, and mutually exclusive mutations of BRAF and NRAS have also been reported in melanomas. In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades. Twelve cell lines, six melanoma and six endometrial cancer, were analyzed; 4 (67%) of the 6 melanomas had gene mutations in the RAS/MAPK cascade, and a decrease or loss of PTEN expression was also observed. These results suggested that simultaneous up-regulations in these two cascades play important roles in carcinogenesis of melanocytes. However, no activation of AKT by phosphorylation was observed. On the other hand, 4 (67%) of the 6 endometrial cancer cell lines had mutually exclusive up-regulations in these cascades. However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6. These results suggest that simultaneous up-regulation of RAS/MAPK and PI3K/AKT cascades are crucial events in the pathogenesis of melanocytes, whereas up-regulation of either the RAS/MAPK or PI3K/AKT cascade is crucial for the majority of endometrial cancers.     

Fisetin,a phytochemical,potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells

Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.     

The study of resistant mechanisms and reversal in an imatinib resistant Ph+ acute lymphoblastic leukemia cell line

In this study, we established an imatinib resistant Ph+ acute lymphoblastic leukemia (ALL) cell line SUP-B15/RI in vitro and studied the mechanism of imatinib resistance. Our results showed that the BCR-ABL1 fusion gene and the mdr1 gene were 6.1 times and 1.7 times, respectively, as high as that of parental SUP-B15 cell line. We found no mutation in the Abl kinase domain of SUP-B15/RI. Furthermore, the detection of cell signaling pathway of PI3K/AKT/mTOR, RAS/RAF, NF-κB, JNK and STAT showed the up-regulation of phosphorylation of AKT, mTOR, P70S6K, and RAF, ERK, and MEK, down-regulation of PTEN and 4EBP-1, and no change in other cell signaling pathways in SUP-B15/RI. However, dasatinib and nilotinib showed partial resistance. Interestingly, bortezomib had no resistance. Imatinib combination with rapamycin had synergistic effect on overcoming the resistance. Altogether, over-expression of BCR-ABL1 and mdr1 gene were involved in the resistance mechanisms, and up-regulation of the cell signaling pathways of PI3K/AKT/mTOR, RAS/RAF in SUP-B15/RI cell line may be correlated with them. The SUP-B15/RI cell line was also resistant to the second generation tyrosine kinase, dasatinib, and nilotinib, not bortezomib. The combination of imatinib with rapamycin can partially overcome the resistance and blockade of the ubiquitin-proteasome can be also a promising pathway to overcome imatinib resistance.     

The dual PI3K/mTOR inhibitor PI‐103 promotes immunosuppression,in vivo tumor growth and increases survival of sorafenib‐treated melanoma cells

Melanoma is the most lethal human skin cancer. If metastatic, it becomes very aggressive and resistant to standard modalities of anticancer treatment. During the last 10 years, several therapeutic strategies have been tested including the use of single and combined small drugs. Experimental results indicate that RAS and PI3K pathways are important for the development and maintenance of melanoma. In this study, we assessed the in vitro and in vivo inhibition potential of PI‐103, a PI3K (p110α)/mTOR inhibitor and sorafenib, a BRAF inhibitor, as single agents and in combination in primary melanoma cell lines. Although PI‐103 and sorafenib inhibited melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway appeared to be more effective. The combination of the two agents in in vitro showed a synergistic effect inhibiting RAS and PI3K pathways in a cell line dependent manner. However, no cooperative effect was observed in blocking in vivo tumor growth in immunocompetent mice. In contrary to the expected, the data indicate that PI‐103 induced immunosuppression promoting in vivo tumor growth and inhibiting apoptosis. Furthermore, in vitro studies examining the effects of the PI3K/mTOR inhibitor in tumor derived cell lines indicated that PI‐103 induced the anti‐apoptotic BH3 family proteins Mcl1, Bcl2 and Bcl_xL favoring, the in vitro survival of sorafenib treated melanoma cells. These data certainly makes an argument for investigating unexpected effects of rational drug combinations on immunocompetent animal models prior to conducting clinical studies.     

Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells

PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated in both primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-ras(G12D/WT) mice with the prostate conditional Pten deletion model. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penetrance. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a mitogen-activated protein (MAP)-extracellular signal-regulated (ER) kinase (MEK) inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, our findings indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis, and cotargeting both the pathways is highly effective in preventing the development of metastatic prostate cancers.     

The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition

Background:

Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines.

Methods:

Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines.

Results:

All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. The reduced synergy exhibited by NVP-BEZ235 in combination with MEK inhibitors, compared with GDC-0941, may be due to inhibition of mTOR, and the addition of the mTORC1/2 inhibitor KU0063794 compromised the synergy of GDC-0941:PD0325901 combinations.

Conclusion:

These studies confirm that dual targeting of PI3K and MEK can induce synergistic growth inhibition; however, the combination of specific PI3K inhibitors, rather than dual mTOR/PI3K inhibitors, with MEK inhibitors results in greater synergy.     

Analysis of cabazitaxel‐resistant mechanism in human castration‐resistant prostate cancer

Cabazitaxel (CBZ) is approved for docetaxel‐resistant castration‐resistant prostate cancer (CRPC). However, efficacy of CBZ for CRPC is limited and there are no effective treatments for CBZ‐resistant CRPC. In order to investigate the CBZ‐resistant mechanism, the establishment of a CBZ‐resistant cell line is urgently needed. We established CBZ‐resistant CRPC cell lines DU145CR and PC3CR by incubating DU145 and PC3 cells with gradually increasing concentrations of CBZ for approximately 2 years. We analyzed the gene expression profiles and cell cycle changes using microarray and flow cytometry. Pathway analysis revealed DU145CR cells had enhanced gene clusters of cell division and mitotic nuclear division. Enhancement of ERK signaling was detected in DU145CR cells. DU145CR cells had resistance to G₂/M arrest induced by CBZ through ERK signaling activation. The MEK inhibitor PD184352 significantly inhibited cell proliferation of DU145CR. In contrast to DU145CR, PC3CR cells had enhancement of PI3K/AKT signaling. The PI3K/mTOR inhibitor NVP‐BEZ 235 had a significant antitumor effect in PC3CR cells. Cabazitaxel ‐resistant CRPC cells established in our laboratory had enhancement of cell cycle progression signals and resistance to G₂/M arrest induced by CBZ. Enhancement of ERK signaling or PI3K/AKT signaling were detected in the cell lines, so ERK or PI3K/AKT could be therapeutic targets for CBZ‐resistant CRPC.     

L744,832 and Everolimus Induce Cytotoxic and Cytostatic Effects in Non-Hodgkin Lymphoma Cells

Non-Hodgkin Lymphoma (NHL) constitutes a very heterogeneous group of diseases with different aggressiveness. Diffuse large B-cell lymphoma (DLBCL) and Burkitt’s lymphoma (BL) are two clinically aggressive lymphomas from the germinal center, very heterogeneous and with different genetic signatures. Several intracellular pathways are involved in lymphomagenesis, being BCR/PI3K/AKT/mTOR and RAS/RAF pathways the most frequently ones. In this context the therapeutic potential of a mTOR inhibitor – everolimus – and a RAS/RAF pathway inhibitor – L744,832 – was evaluated in two NHL cell lines. Farage and Raji cells were cultured in the absence and presence of several concentrations of everolimus and L744,832 in monotherapy and in combination with each other, as well as in association with the conventional chemotherapy drug vincristine. Our results show that everolimus and L744,832 induce antiproliferative and cytotoxic effect in a time-, dose-, and cell line-dependent manner, inducing cell death mainly by apoptosis. A potentiation effect was observed when the drugs were used in combination. In conclusion, the results suggest that everolimus and L744,832, alone or in combination, could provide therapeutic benefits in these subtypes of NHL.     

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.     

Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY‐142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines

Mutations in KRAS or BRAF frequently manifest in constitutive activation of the MEK1/2‐ERK1/2 signalling pathway. The MEK1/2‐selective inhibitor, AZD6244 (ARRY‐142886), blocks ERK1/2 activation and is currently undergoing clinical evaluation. Tumour cells can vary markedly in their response to MAPK or ERK kinase (MEK) inhibitors, and the presence of a BRAF mutation is thought to predict sensitivity, with the RAS mutations being associated with intrinsic resistance. We analysed cell proliferation in a panel of 19 colorectal cancer cell lines and found no simple correlation between BRAF or KRAS mutation and sensitivity to AZD6244, though cells that harbour neither mutation tended to be resistant. Cells that were sensitive arrested in G₁ and/or underwent apoptosis and the presence of BRAF or KRAS mutation was not sufficient to predict either fate. Cell lines that were resistant to AZD6244 exhibited low or no ERK1/2 activation or exhibited coincident activation of ERK1/2 and protein kinase B (PKB), the latter indicative of activation of the PI3K pathway. In cell lines with coincident ERK1/2 and PKB activation, sensitivity to AZD6244 could be re‐imposed by any of the 3 distinct PI3K/mTOR inhibitors. We conclude that AZD6244 is effective in colorectal cancer cell lines with BRAF or KRAS mutations. Sensitivity to MEK1/2 inhibition correlates with a biochemical signature; those cells with high ERK1/2 activity (whether mutant for BRAF or KRAS) evolve a dependency upon that pathway and tend to be sensitive to AZD6244 but this can be offset by high PI3K‐dependent signalling. This may have implications for the use of MEK inhibitors in combination with PI3K inhibitors. © 2009 UICC     

Sensitivity of glioblastomas to clinically available MEK inhibitors is defined by neurofibromin 1 deficiency

Loss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor-sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor-sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials.     

Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors

BackgroundOvarian cancer is the major cause of death from gynaecological malignancy with a 5 year survival of only ～30% due to resistance to platinum and paclitaxel-based first line therapy. Dysregulation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) and RAS/extracellular signal-regulated kinase (ERK) pathways is common in ovarian cancer, providing potential new targets for 2nd line therapy.MethodsWe determined the inhibition of proliferation of an extensive panel of ovarian cancer cell lines, encompassing all the major histotypes, by the dual PI3K/mTOR inhibitor PF-04691502 and a MEK inhibitor, PD-0325901. In addition, we analysed global gene expression, mutation status of key PI3K/mTOR and RAS/ERK pathway members and pathway activation to identify predictors of drug response.ResultsPF-04691502 inhibits proliferation of the majority of cell lines with potencies that correlate with the extent of pathway inhibition. Resistant cell lines were characterised by activation of the RAS/ERK pathway as indicated by differential gene expression profiles and pathway activity analysis. PD-0325901 suppressed growth of a subset of cell lines that were characterised by high basal RAS/ERK signalling. Strikingly, using PF-04691502 and PD-0325901 in combination resulted in synergistic growth inhibition in 5/6 of PF-04691502 resistant cell lines and two cell lines resistant to both single agents showed robust synergistic growth arrest. Xenograft studies confirm the utility of combination therapy to synergistically inhibit tumour growth of PF-04691502-resistant tumours in vivo.ConclusionsThese studies identify dual targeted inhibitors of PI3K/mTOR in combination with inhibitors of RAS/ERK signalling as a potentially effective new approach to treating ovarian cancer.     

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.     

Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway

Background

Most targeted anticancer therapies, as well as cytotoxic and radiation therapies, are encumbered by the development of secondary resistance by cancer cells. Resistance is a complex phenomenon involving multiple mechanisms, including activation of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR). Novel strategies to overcome resistance by targeting these signaling pathways are being evaluated.

Methods

PubMed and key cancer congress abstracts were searched until July 2012 for preclinical and clinical data relating to the PI3K/AKT/mTOR pathway and anticancer treatment resistance, and use of PI3K/AKT/mTOR inhibitors in resistant cancer cell lines and patient populations.

Results

Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors, radiation, and cytotoxics. As such, inhibitors of the PI3K/AKT/mTOR pathway are being rapidly evaluated in preclinical models and in clinical studies to determine whether they can restore therapeutic sensitivity when given in combination. In breast cancer, non-small-cell lung cancer, and glioblastoma, we find compelling preclinical evidence to show that inhibitors of PI3K or mTOR can restore sensitivity in resistant cells. Although clinical evidence is less mature, a recent Phase III study with the mTORC1 inhibitor everolimus in patients with advanced breast cancer resistant to aromatase inhibition and several Phase I/II studies with PI3K inhibitors demonstrate proof-of-concept, warranting future clinical evaluation.

Conclusion

Current preclinical and clinical evidence suggest that inhibitors of the PI3K/AKT/mTOR pathway could have utility in combination with other anticancer therapies to circumvent resistance by cancer cells. Multiple clinical studies are ongoing.