{"id":4314,"date":"2025-09-12T15:37:09","date_gmt":"2025-09-12T19:37:09","guid":{"rendered":"https:\/\/happylungsproject.org\/?p=4314"},"modified":"2026-03-02T10:52:36","modified_gmt":"2026-03-02T15:52:36","slug":"ret-studies-presented-at-the-iaslc-2025-world-conference-on-lung-cancer","status":"publish","type":"post","link":"https:\/\/happylungsproject.org\/ret-studies-presented-at-the-iaslc-2025-world-conference-on-lung-cancer\/","title":{"rendered":"RET Studies Presented at the IASLC 2025 World Conference on Lung Cancer"},"content":{"rendered":"[vc_row type=”in_container” full_screen_row_position=”middle” column_margin=”default” column_direction=”default” column_direction_tablet=”default” column_direction_phone=”default” scene_position=”center” text_color=”dark” text_align=”left” row_border_radius=”none” row_border_radius_applies=”bg” overflow=”visible” overlay_strength=”0.3″ gradient_direction=”left_to_right” shape_divider_position=”bottom” bg_image_animation=”none” shape_type=””][vc_column column_padding=”no-extra-padding” column_padding_tablet=”inherit” column_padding_phone=”inherit” column_padding_position=”all” column_element_direction_desktop=”default” column_element_spacing=”default” desktop_text_alignment=”default” tablet_text_alignment=”default” phone_text_alignment=”default” background_color_opacity=”1″ background_hover_color_opacity=”1″ column_backdrop_filter=”none” column_shadow=”none” column_border_radius=”none” column_link_target=”_self” column_position=”default” gradient_direction=”left_to_right” overlay_strength=”0.3″ width=”1\/1″ tablet_width_inherit=”default” animation_type=”default” bg_image_animation=”none” border_type=”simple” column_border_width=”none” column_border_style=”solid”][vc_row_inner column_margin=”default” column_direction=”default” column_direction_tablet=”default” column_direction_phone=”default” text_align=”left” row_position=”default” row_position_tablet=”inherit” row_position_phone=”inherit” overflow=”visible” pointer_events=”all”][vc_column_inner column_padding=”padding-3-percent” column_padding_tablet=”inherit” column_padding_phone=”inherit” column_padding_position=”all” column_element_direction_desktop=”default” column_element_spacing=”default” desktop_text_alignment=”default” tablet_text_alignment=”default” phone_text_alignment=”default” background_color=”#f68d28″ background_color_opacity=”1″ background_hover_color_opacity=”1″ column_backdrop_filter=”none” font_color=”#ffffff” column_shadow=”none” column_border_radius=”10px” column_link_target=”_self” overflow=”visible” gradient_direction=”left_to_right” overlay_strength=”0.3″ width=”1\/1″ tablet_width_inherit=”default” animation_type=”default” bg_image_animation=”none” border_type=”simple” column_border_width=”none” column_border_style=”solid” column_padding_type=”default” gradient_type=”default”][vc_column_text css=”” text_direction=”default”]The 2025 IASLC World Conference on Lung Cancer was held in Barcelona, Spain, from September 6\u20139, where some important studies on RET were presented.[\/vc_column_text][\/vc_column_inner][\/vc_row_inner][vc_row_inner column_margin=”default” column_direction=”default” column_direction_tablet=”default” column_direction_phone=”default” text_align=”left” row_position=”default” row_position_tablet=”inherit” row_position_phone=”inherit” overflow=”visible” pointer_events=”all”][vc_column_inner column_padding=”no-extra-padding” column_padding_tablet=”inherit” column_padding_phone=”inherit” column_padding_position=”all” column_element_direction_desktop=”default” column_element_spacing=”default” desktop_text_alignment=”default” tablet_text_alignment=”default” phone_text_alignment=”default” background_color_opacity=”1″ background_hover_color_opacity=”1″ column_backdrop_filter=”none” column_shadow=”none” column_border_radius=”none” column_link_target=”_self” overflow=”visible” gradient_direction=”left_to_right” overlay_strength=”0.3″ width=”1\/1″ tablet_width_inherit=”default” animation_type=”default” bg_image_animation=”none” border_type=”simple” column_border_width=”none” column_border_style=”solid”][vc_column_text css=”” text_direction=”default”]P3.03.12\u00a0<\/span><\/strong><\/span><\/p>\n

YAP-Driven Modulation of HER3-Mediated Adaptive Resistance to RET Inhibitors in RET-Altered Cancer<\/h3>\n

Tadaaki Yamada<\/strong><\/p>\n

This study investigates mechanisms of resistance to RET tyrosine kinase inhibitors (RET-TKIs) in RET-altered cancers, particularly lung and thyroid cancers harboring RET fusions or mutations.\u00a0<\/span><\/p>\n

This study showed that adaptive resistance to RET TKIs emerges via reactivation of ERK signaling mediated by HER3 activation following RET-TKI treatment. YAP, a key Hippo pathway effector, is translocated to the nucleus upon RET inhibition, driving HER3 gene expression and thus enabling ERK reactivation and resistance. Cell lines with high YAP expression display reduced sensitivity to RET-TKIs, whereas YAP knockdown suppresses proliferation, suggesting YAP as a potential biomarker for RET-TKI responsiveness.<\/p>\n

Importantly, combining the pan-HER inhibitor afatinib with selpercatinib effectively suppresses ERK reactivation and cell proliferation in RET-TKI resistant, YAP-high cancer cells in vitro and in vivo. This combination therapy shows superior tumor control compared to single agents.<\/p>\n

Clinical analysis of 23 RET-positive non-small cell lung cancer patients treated with selpercatinib indicates that low intratumoral cytoplasmic YAP expression correlates with longer progression-free and overall survival, supporting YAP\u2019s role as a predictive biomarker.<\/p>\n

In conclusion, YAP-driven HER3 activation constitutes a key adaptive resistance mechanism to RET-TKIs. Early combination therapy targeting both RET and HER3 pathways may overcome resistance, and assessing tumor YAP levels can guide treatment stratification for improved outcomes in RET-altered cancers.<\/p>\n

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P3.03.49<\/b><\/span><\/p>\n

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer Cells Harbouring RET Fusions<\/h3>\n

Eva Pros<\/strong><\/p>\n

In this study, researchers created RET-fusion lung cancer cells that became resistant to RET inhibitors using 2 RET cancer cell lines: LC-2 and PDC6. They found that in these cell lines, resistance arise mainly from the activation of other growth pathways (AKT, ERK, mTOR) or the development of new mutations in KRAS or NRAS genes. Some cells also developed a brand-new gene fusion that helped them survive.<\/p>\n

These results show that RET-positive lung cancers often escape treatment by turning on backup pathways, meaning combination therapies will likely be needed to block resistance and improve outcomes.<\/p>\n

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P3.12.06\u00a0<\/span><\/b><\/p>\n

Pralsetinib (Phase 1\/2 ARROW Trial) Compared With Best Available Therapy (External Control) in Pretreated RET Fusion+ NSCLC<\/b><\/h3>\n

Domenico Galetta<\/strong><\/p>\n

This study compares the outcomes of pralsetinib, to best available therapy (BAT) (tyrosine kinase inhibitors (e.g., cabozantinib, vandetanib) and chemotherapy) in patients with previously treated, advanced RET fusion-positive lung cancer, using data from the Phase 1\/2 ARROW trial and a real-world (RW) external control cohort.\u00a0<\/span><\/p>\n

Key findings:<\/p>\n