As integration between the tumor suppressive and oncogenic signaling pathways regulate cancer cell activities, including cell growth and apoptosis, understanding the mechanistic insights will provide approaches to overcome drug resistance and improve the efficacy of therapeutic agents. Among tumor suppressor family members, the phosphatase and tensin homolog (PTEN) plays an important role in mediating lipid phosphatase activity that antagonizes phosphatidylinositol 3-kinase (PI3K) resulting in the inhibition of the downstream mammalian target of the rapamycin (mTOR)/AKT signaling pathway [1–3]. The PTEN functions have been extensively studied in various cell culture systems, preclinical models, and clinical settings of malignancies, including lung cancer [4–6], and reviewed in reference [7]. Notably, reduced expression or loss of tumoral PTEN is associated with the overall low survival of cancer patients. Thus, approaches to overcome this effect would aid in the ongoing challenges of cancer treatment, including non-small cell lung cancer (NSCLC) [4, 6, 7]. As PTEN remains an undruggable target, strategies to modulate its activity via targeting counteracting pathways such as platelet-activating factor-receptor (PAFR) signaling are being explored as potential approaches to overcome therapeutic resistance.

The PAFR signaling plays critical roles in various physiological and pathophysiological conditions, including cancer [8–11]. Notably, clinical studies demonstrated that high tumoral-PAFR expression correlates with increasing tumor stages/invasiveness, poor prognosis, and decreased overall survival in lung and esophageal squamous cell carcinoma patients [12, 13]. Of significance, increased levels of PAF agonists or PAFR activity have been detected in perfusates and tumor samples collected post-chemotherapy and post-radiation therapy compared to pre-chemotherapy and pre-radiation therapy in melanoma and non-melanoma patients [9, 14]. Along similar lines, da Silva-Jr et al. [8] reported high levels of PAFR expression in tumor samples collected from cervical invasive carcinoma patients treated with radiotherapy compared to untreated patients. This indicated that understanding the insights into the PAFR pathway and its crosstalk with potential signaling mechanisms such as epidermal growth factor receptor (EGFR) could provide potential target(s) to be explored against malignancies, including NSCLC.

Importantly, receptor tyrosine kinases (RTK) such as EGFR signaling play critical roles in modulating the cellular activities of tumor cells, including cell proliferation [15, 16]. Its overactivation or mutations also account for the acquired tumor resistance and/or reduced efficacy of tyrosine kinase inhibitors (TKIs) in preclinical experimental models, and cancer patients, reviewed in references [16, 17]. The generations of EGFR-TKIs are based on their characteristics and the order they were developed [18]. For example, the first-generation EGFR-TKIs are reversible EGFR inhibitors such as erlotinib and gefitinib. The second generation includes irreversible erythroblastic leukemia viral oncogene homolog (ErbB) family blockers, including EGFR such as afatinib and dacomitinib, which were designed to overcome resistance to first-generation EGFR-TKIs. The third-generation EGFR-TKIs include irreversible EGFR mutant selective and wild-type (WT) EGFR sparing such as osimertinib for patients with T790M acquired resistant mutation [19]. However, patients can develop resistance to these EGFR-TKIs via mechanisms mediated by both EGFR-dependent and EGFR-independent pathways [20, 21]. While there was ample evidence about the roles and mechanisms of the PTEN, PAFR, and EGFR pathways, there was no published review article that highlights the impact of the crosstalk between the PTEN and PAFR as well as the PAFR and EGFR pathways in cancer models, which was the goal of this minireview. As PTEN inactivation is associated with resistance to EGFR-TKIs, we anticipated that PAFR could be involved as a central mechanism in mediating inactivated PTEN-induced EGFR overactivation, and thus, could be exploited as a potential target to overcome EGFR-TKIs resistance.

The generation of reactive oxygen species (ROS) is one of the common mechanisms of pro-oxidative stressors, including radiation therapy and chemotherapeutic agents [8, 9]. Studies, including ours, provided compelling evidence that such ROS-generating agents, produce oxidized phospholipid mediators, PAF, and PAF-like agonists, which bind to and activate a G-protein coupled PAFR, expressed on a variety of cell types, including tumor cells [8, 9, 22–24]. Besides, PAF agonists are also synthesized via highly regulated remodeling and de novo pathways involving cytosolic phospholipase A₂ (cPLA₂), acetyltransferase, and acetylhydrolase enzymes [22–24]. The roles and mechanisms of the PAF-PAFR signaling in mediating acute pro-inflammatory and delayed chronic responses, including systemic immunosuppression and cancer growth have been studied and reviewed in references [10, 11]. The immune cell types implicated in PAF-PAFR mediated systemic immunosuppressive effects include CD4+CD25+FoxP3+ regulatory T cells (Tregs), CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), and CD163+, CD206+, Arg1+ tumor-associated macrophages (TAMs) [8, 9, 24, 25]. Notably, these immunosuppressive cell types also play critical roles in augmenting tumor growth or impeding the efficacy of therapeutic agents in experimental cancer models, including NSCLC [8, 9, 12, 25, 26]. Importantly, pharmacological inhibitors of cyclooxygenase type 2 (COX-2) or depleting antibodies against Tregs attenuate PAFR-mediated systemic immunosuppression, and tumor growth, as well as enhance the efficacy of chemotherapeutic agents and radiation therapy in experimental cancer models [9, 14]. These experimental findings indicated that therapeutic agents can produce PAF agonists, which mediate pro-tumoral responses, and impede the efficacy of cancer therapies in a PAFR-dependent manner.

Given that PAF-metabolizing, PAF-acetylhydrolase (PAF-AH) can readily metabolize PAF agonists, a question as to how PAF agonists mediate delayed systemic immunosuppression and pro-tumoral effects remained unanswered. To that end, our recent studies determined the significance of a subpopulation of extracellular vesicles referred to as microvesicles, large extracellular vesicles, or microvesicle particles (MVPs). Our studies demonstrated that gemcitabine treatment for PANC-1 pancreatic cancer cells generates MVPs in a PAFR-dependent manner and that these MVPs contain PAF agonists [27]. Along similar lines, we have shown that targeted therapies, gefitinib and erlotinib treatment to A549 and H1299 NSCLC cell lines produce MVP release in a PAFR-dependent manner, in a process blocked by PAFR antagonist or PAFR silencing [28]. As the biosynthesis of MVP requires the activation and translocation of an acid sphingomyelinase (aSMase), our studies demonstrated that an aSMase-specific inhibitor, imipramine blocks targeted therapy-induced MVP release in NSCLC cells [28]. These findings highlighted the relevance of PAFR signaling in therapeutic agents-induced MVP release, which acts as a novel mechanism by which metabolically labile PAF agonists are not only protected but circulated to exert local as well as delayed systemic effects. Importantly, as PTEN crosstalks with several oncogenic signaling cascades to regulate the growth/fate of tumor cells, including NSCLC, herein, we discussed the key findings, highlighting the crosstalk of the PTEN and PAFR pathways, and PAFR and EGFR pathways and their significance in cancer and cancer therapies.

PTEN targets the PAFR signaling, which interacts with EGFR and its downstream cascades, and PAFR/EGFR blockade has been shown to inhibit the growth of tumor cells. While the interaction between the PTEN, PAFR, and EGFR pathways remains elusive, the consummated findings provide compelling evidence that the PTEN-PAFR and PAFR-EGFR axis (and their downstream cascades) represent novel targets for malignancies, including NSCLC. Given that malignant cells develop resistance to currently used EGFR-TKIs, and PAFR can mediate inactivated PTEN-induced EGFR overactivation, targeting PAFR could be exploited as a potential strategy to overcome EGFR-TKIs resistance in cancer patients having altered/mutated EGFR. Overall, these findings suggested that pharmacological approaches to target these pathways could also be explored to mitigate therapy-induced adverse events and enhance therapy effectiveness.