ERBB family members including epidermal growth factor receptor (EGFR) also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs). Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib) or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

The ERBB family of receptor tyrosine kinases has been implicated in carcinogenesis for over three decades with rigorous attention to EGFR and HER2. ERBB receptors, consisting of EGFR, HER2, HER3, and HER4 are part of a complicated signaling network that activates downstream signaling pathways including PI3K/AKT, Ras/Raf/MAPK, JAK/STAT and PKC. It is well established that EGFR is amplified and/or mutated in gliomas and non-small-cell lung carcinoma while HER2 is amplified and/or over-expressed in breast, gastric, ovarian, non-small cell lung carcinoma, and several other tumor types. With the advent of next generation sequencing and large scale efforts to explore the entire spectrum of genomic alterations involved in human cancer progression, it is now appreciated that somatic ERBB receptor mutations occur at relatively low frequencies across multiple tumor types. Some of these mutations may represent oncogenic driver events; clinical studies are underway to determine whether tumors harboring these alterations respond to small molecule EGFR/HER2 inhibitors. Recent evidence suggests that some somatic ERBB receptor mutations render resistance to FDA-approved EGFR and HER2 inhibitors. In this review, we focus on the landscape of genomic alterations of EGFR, HER2, HER3 and HER4 in cancer and the clinical implications for patients harboring these alterations.

We conclude that PI3K-dependence varies with stimulus and response, and that eotaxin-induced eosinophil migration is not controlled by PI3K. This may indicate a limit to the potential of PI3K inhibitors to suppress tissue eosinophilia in diseases such as asthma.