Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer. Significance: The difficulty in collection of transformation samples has precluded the performance of molecular analyses, and thus little is known about the lineage plasticity mechanisms leading to LUAD-to-SCLC transformation. Here, we describe biological pathways dysregulated upon transformation and identify potential predictors and potential therapeutic vulnerabilities of NE transformation in the lung. See related commentary by Meador and Lovly, p. 2962. This article is highlighted in the In This Issue feature, p. 2945
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1, as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC, with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease. Significance: CRISPR-Cas9 screening nominates exportin-1 as a therapeutic target in SCLC, and exportin-1 inhibition enhances chemotherapy efficacy in patient-derived xenografts, providing a novel therapeutic opportunity in this disease.
561 Background: PBRM1 and BAP1, both of which encode chromatin modulating proteins, have recently been identified as frequently mutated tumor suppressor genes in RCC. However, their correlation with outcomes of targeted therapies is unknown. We explored correlations between overall survival (OS) and mutations in archival tumor samples from RECORD-3, a randomized phase 2 trial comparing first-line everolimus (EVE) then sunitinib (SUN) to first-line SUN then EVE at progression in 471 treatment-naïve mRCC patients (J Clin Oncol 2014; 32:2764). Methods: Somatic mutations in exons of 341 cancer related genes were identified by a next generation sequencing (NGS) assay (MSK IMPACT). Association between genotypes and OS was assessed by Cox PH models and log-rank tests. Results: DNA of 258 archival tumor and 181 matched germline samples was successfully analyzed (median coverage 530X). Three molecular subgroups Gr1 (BAP1 MT [mutant], PBRM1 WT [wild-type]/MT; 17.4%), Gr2 (PBRM1 MT, BAP1 WT; 38.4%), and Gr3 (PBRM1 WT, BAP1 WT; 44.2%) with different OS outcomes after sequential EVE-SUN or SUN-EVE were identified (Table). In the sequential EVE-SUN arm, median OS (months) was shortest with Gr1 (9.8; 95% CI, 7.8–20.0), longest with Gr2 (39.6; 95% CI, 31.7–not estimable), and intermediate with Gr3 (18.1; 13.7–30.0), whereas in the SUN-EVE arm there was no significant difference among groups. When comparing OS between treatment sequences within molecular groups, a trend suggested differences for EVE-SUN vs SUN-EVE in Gr1 (HR 1.5), Gr2 (0.8), and Gr3 (1.2), although comparisons were not statistically significant. Conclusions: Our results suggest that these genotypes may represent distinct RCC molecular subtypes with potentially different predictive/prognostic values on targeted therapies. Different treatment sequences may be considered depending on the genotypes. Clinical trial information: NCT00903175. [Table: see text]
Small cell lung cancer (SCLC) is an aggressive disease characterized by early metastasis and exceptional lethality, comprising 13% of all lung cancer cases. With few treatment options, typically resulting in only transient responses, SCLC is responsible for approximately 250,000 deaths globally per year. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy to first-line chemotherapy showing limited benefit in a small subset of patients. Major hurdles to improving SCLC treatment include development of rapid chemoresistance and ineffective second line therapies. The identification of more durably effective therapeutic strategies is a major unmet clinical need. Here, we performed an in vitro CRISPR screen in SCLC cell lines from all major SCLC subtypes, including short-term cultured cells from patient-derived xenografts (PDXs), to identify potential therapeutic targets to enhance sensitivity to chemotherapy. Candidate hits were validated genetically and pharmacologically with in vitro synergy assays, in vivo clonal competition assays and pharmacologic assessments in PDX models. Signaling pathways were studied by RNA sequencing and western blot, and toxicity studies were performed in vivo to assess the safety of the agents at pharmacologically effective doses. We performed immunohistochemistry (IHC) to assess expression of candidate targets in tissue microarrays (TMAs). Our CRISPR screen revealed the nuclear exporter exportin 1 (encoded by the XPO1 gene) as a promising target sensitizing to chemotherapy, independently of the SCLC subtype. We found that XPO1 mRNA expression was higher in SCLC than in any other solid tumor or hematological malignancy, and demonstrated consistently high protein expression by IHC in clinical TMAs. A potent and selective exportin 1 inhibitor, selinexor, is approved for use in hematological malignancies. Combination of selinexor with cisplatin or irinotecan demonstrated synergy in vitro and efficacy in vivo in an array of chemonäive and chemoresistant SCLC PDXs, including all major SCLC subtypes. The combinations were well tolerated in mice. The chemo-sensitizing effects of selinexor were associated with suppression of chemotherapy-induced AKT activation. In conclusion, exportin 1 inhibition strongly enhances sensitivity of SCLC tumors to cisplatin and irinotecan, used in first line and second line treatment of SCLC tumors, respectively, and these effects are independent of the SCLC subtype. These results provide preclinical rationale for the combination of selinexor with cisplatin or irinotecan in naïve and relapsed SCLC. The clinical availability of selinexor will allow rapid clinical translation of these results in a disease setting with extremely limited therapeutic options. Citation Format: Alvaro Quintanal-Villalonga, Hirokazu Taniguchi, Yuan Hao, Andrew Chow, Yingqian A. Zhan, Fathema Uddin, Viola Allaj, Parvathy Manoj, Nisargbhai S. Shah, Umesh K. Bhanot, Juan Qiu, Elisa de Stanchina, Richard P. Koche, Triparna Sen, John T. Poirier, Charles M. Rudin. Exportin 1 inhibition as a therapeutic strategy for small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3594.
BackgroundWe identified somatic PIK3CA mutations in 32.5% of 590 primary invasive breast cancers (BC) (manuscript in press: Clinical Cancer Research). Detected by massARRAY genotyping, PIK3CA mutations significantly associate with favorable clinicopathologic features and improved clinical outcome, including overall and breast cancer-specific survival. Given the strong association between PIK3CA mutations and hormone receptor (HR) positivity, one hypothesis is that PIK3CA mutations 'drive' HR positive BC and will be detected in pre-invasive breast tumors. As PIK3CA mutations offer a protective effect in BC, it has not been determined whether PIK3CA mutations are selected for in disease progression or whether additional collaborating mutations are required.MethodsTo determine the concordance of PIK3CA mutations and assess the acquisition of additional oncogene mutations, available matched tissue samples, from the previous database, were procured and underwent massARRAY genotyping (n = 83). Two mm cores were macro-dissected from matched formalin-fixed, paraffin embedded tissue, including normal breast tissue, benign lymph nodes (LN), ductal carcinoma-in-situ (DCIS), regional LN metastases (mets), and distant mets. MassARRAY (Sequenom) genotyping was performed on native DNA to identify rare and hotspot PIK3CA mutations, as well as AKT1 (E17K), RAS, and RET mutations.ResultsConcordance of PIK3CA mutations is noted between primary BC and DCIS, except for one rare PIK3CA mutation (Q546R) not detected in DCIS (4/5). No PIK3CA mutations are detected in normal breast tissue (0/8) or benign LN (0/6). Rare and hotspot PIK3CA mutations in primary BC are detected in 87.5% (7/8) matched regional LN met and 80 % (4/5) distant mets. For the patient with the disconcordant regional LN met, the rare PIK3CA mutation (H1047L) identified in primary BC is also present in the distant met site. Notably, for the single disconcordant PIK3CA met site, a rare PIK3CA mutation (E545A) is detected in a primary tumor, regional LN met, and bone met and is absent in a second bone met, in which a KRAS (G12C) mutation has been identified. One concomitant hotspot PIK3CA (E542K)/KRAS (G12C) mutation is present in both primary BC and paired DCIS. Complete concordance of AKT1 (E17K) mutations has been identified between in DCIS, primary BC, regional LN met, and distant mets (n=4).ConclusionsWe recently defined the positive prognostic significance of PIK3CA mutations in breast cancer. PIK3CA and AKT1 (E17K) mutations are early events in breast cancer, occurring in pre-invasive tumors. Despite the protective effect of PIK3CA mutations on clinical outcome, they persist and are selected for in disease progression, as they are detected in regional LN and distant mets. Complete concordance is identified between hotspot PIK3CA mutated primary BC and matched tumors samples, suggesting that PIK3CA mutations with higher oncogenic potency are maintained in tumor progression. These findings support that targeting the PI3K pathway may assist in tailoring therapy to appropriate patient populations. We are expanding matched tissue collection from a separate patient cohort to further assess genomic and functional genomic change with disease progression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5164.
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Pancreatic ductal adenocarcinoma (PDAC) is the classic cold tumor, with few tumor-infiltrating activated CD8+ T cells, a major barrier to immunotherapy. Strategies to convert cold PDACs to hot can enable more effective immunotherapies. To identify targets that can convert cold PDACs to hot, we compared a large cohort of rare long-term PDAC survivors with hot tumors to short-term survivors with cold tumors. Surprisingly, hot PDACs were enriched not only in activated CD8+ T cells, but also in group-2 innate lymphoid cells (ILC2s), a class of largely tissue-resident, cytokine-producing innate lymphocyte that potentiates T cell immunity in local tissues. We identified that tumor ILC2s (TILC2s) infiltrate human and mouse PDACs, and TILC2 frequency and tumor expression of the ILC2-activating ligand interleukin (IL)-33 positively correlate with tumor immune cytolytic activity, and long-term patient survival. Using PDAC mouse models, we discovered that the IL33-ILC2 axis activates pancreatic tissue-specific antitumor T-cell immunity. Host IL33 deficiency attenuated TILC2 expansion and CD8+ T-cell activation, accelerating tumor growth in orthotopic PDACs but not heterotopic skin implanted PDACs where TILC2s lack the IL33 receptor. Acute ILC2 depletion partially phenocopied the tissue-specific phenotype of IL33 deficiency, with impaired rejection of immunogenic orthotopic but not heterotopic skin PDACs. Treatment with recombinant IL33 (rIL33), but not with the ILC1-activating ligand rIL18, increased TILC2 frequencies, activated CD8+ T cells, and abrogated orthotopic but not heterotopic PDAC establishment in >70% of mice. Taken together, these studies identify ILC2s as novel anticancer immune cells for PDAC immunotherapy. Strategies to activate tissue-specific ILC2s may be a promising immunotherapeutic approach for PDAC. Citation Format: Joanne Leung, Luis A Rojas, Jennifer Ruan, Julia Zhao, Billel Gasmi, Zachary Sethna, Anita Ramnarain, Umesh Bhanot, Gokce Askan, Murali Gururajan, Ela Elyada, Youngkyu Park, David A. Tuveson, Mithat Gonen, Steven D. Leach, Jedd D. Wolchok, Ronald P. DeMatteo, Taha Merghoub, Vinod P. Balachandran, John Alec Moral. Tissue-specific innate lymphoid cells are novel targets for pancreatic cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B02.
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