Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models. Experimental Design: We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial. Results: SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin–bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient-derived (PDX) subcutaneous xenografts. Selinexor–GEM–nab-paclitaxel blocked PDX and orthotopic tumor growth. In a phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1,000 mg/m2 i.v.) and nab-paclitaxel (125 mg/m2 i.v.) on days 1, 8, and 15 of 28-day cycle. Two patients showed partial response, and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression-free survival of 16 months and overall survival of 22 months. Conclusions: Our preclinical and ongoing clinical study lends support to the use of selinexor–GEM–nab-paclitaxel as an effective therapy for metastatic PDAC.

Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation.

The identification of molecules that can bind covalently to KRAS G12C and lock it in an inactive GDP-bound conformation has opened the door to targeting KRAS G12C selectively. These agents have shown promise in preclinical tumor models and clinical trials. FDA has recently granted approval to sotorasib for KRAS G12C–mutated non–small cell lung cancer (NSCLC). However, patients receiving these agents as monotherapy generally develop drug resistance over time. This necessitates the development of multi-targeted approaches that can potentially sensitize tumors to KRAS inhibitors. We generated KRAS G12C inhibitor–resistant cell lines and observed that they exhibit sensitivity toward selinexor, a selective inhibitor of nuclear export protein exportin 1 (XPO1), as a single agent. KRAS G12C inhibitors in combination with selinexor suppressed the proliferation of KRAS G12C–mutant cancer cell lines in a synergistic manner. Moreover, combined treatment of selinexor with KRAS G12C inhibitors resulted in enhanced spheroid disintegration, reduction in the number and size of colonies formed by G12C-mutant cancer cells. Mechanistically, the combination of selinexor with KRAS G12C inhibitors suppressed cell growth signaling and downregulated the expression of cell-cycle markers, KRAS and NF-κB as well as increased nuclear accumulation of tumor suppressor protein Rb. In an in vivo KRAS G12C cell-derived xenograft model, oral administration of a combination of selinexor and sotorasib was demonstrated to reduce tumor burden and enhance survival. In conclusion, we have shown that the nuclear transport protein XPO1 inhibitor can enhance the anticancer activity of KRAS G12C inhibitors in preclinical cancer models.Significance: In this study, combining nuclear transport inhibitor selinexor with KRAS G12C inhibitors has resulted in potent antitumor effects in preclinical cancer models. This can be an effective combination therapy for patients with cancer that do not respond or develop resistance to KRAS G12C inhibitor treatment.

Perianal Paget’s disease is a rare malignancy. It is rarely isolated and often associated with an underlying adenocarcinoma. It usually presents with anal itchiness and discomfort and can be misdiagnosed as hemorrhoids. Once the diagnosis of perianal Paget’s disease is granted, extensive work-up to find an underlying primary malignancy is crucial. Surgery is the standard modality of treatment of extramammary Paget’s disease (EMPD) with recurrence rates of 44–60%. Other different treatment modalities including radiotherapy, laser therapy, topical and systemic chemotherapy and the new emerging, promising photodynamic therapy are in the field of study. A 76-year-old man was referred to our hospital with a one-year history of anal itchiness and intermittent rectal bleeding. Skin shave and punch biopsies from the perianal area were reported back as perianal Paget’s disease with no underlying adenocarcinoma. The immunohistochemical stains were positive for cytokeratin 7 but also positive for cytokeratin 20 and CEA which indicated the essentiality of extensive investigations to find a primary malignancy. Skin exam showed no primary source. The investigations were unable to find the primary malignancy. Given the results of immunohistochemical stains we recommended local perianal Paget’s disease resection. The intraoperative frozen section showed adenocarcinoma around the anal sphincter. Ten days later the patient underwent an abdominoperineal resection and the final pathology report showed extensive adenocarcinoma in three quadrants of the perianal area with focal involvement of the rectal mucosa. We recommended an adjuvant chemotherapy with FOLFOX following surgery given the bulkiness of the disease. We conclude that once perianal Paget’s disease is diagnosed, an extensive work-up should be done to find the underlying primary malignancy. Immunohistochemical stains are helpful in raising the suspicion of underlying primary malignancy. Finding an underlying primary malignancy in patients with EMPD is prompt to choose the treatment modality and estimate the prognosis.

KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras–driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line–derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.